1-phenyl-substituted heterocyclyl derivatives and their use as prostaglandin d2 receptor modulators

ABSTRACT

The present invention relates to 1-phenyl-substituted heterocyclyl derivatives of the formula (I), 
     
       
         
         
             
             
         
       
     
     wherein X, Y, Z, n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 10  are as described in the description and their use as prostaglandin receptor modulators, most particularly as prostaglandin D 2  receptor modulators, in the treatment of various prostaglandin-mediated diseases and disorders, to pharmaceutical compositions containing these compounds and to processes for their preparation.

FIELD OF THE INVENTION

The present invention relates to 1-phenyl-substituted heterocyclyl derivatives of formula (I) and their use as prostaglandin receptor modulators, most particularly as prostaglandin D₂ receptor (“DP receptor”) modulators, in the treatment of various prostaglandin-mediated diseases and disorders, to pharmaceutical compositions containing these compounds and to processes for their preparation. In particular, such derivatives may be used alone or in pharmaceutical compositions for the treatment of both, chronic and acute allergic/immune diseases/disorders such as asthma, allergic asthma, eosinophilic asthma, severe asthma, rhinitis, allergic rhinitis, angioedema, insect venom allergy, drug allergies, allergic sinusitis, allergic nephritis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, ulcerative colitis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease and rheumatoid arthritis; eosinophil-related diseases comprising small vessel vasculitides like Churg-Strauss syndrome, Wegener's granulomatosis, microscopic polyangiitis (and organ-specific subsets of the latter), hypereosinophilic syndromes like eosinophilic pneumonia, eosinophilic esophagitis, reflux esophagitis, eosinohilic endocarditis (Loeffler's endocarditis), eosinophilia-myalgia syndrome, eosinophilic fasciitis, eosinohilic pustular folliculitis (Ofuji's disease), eosinophilic ulcers, angiolymphoid hyperplasia with eosinophilia (ALHE), eosinophilic cellulitis (Wells syndrome), chronic eosinophilic leukemia and DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms); and basophil-related diseases, comprising basophilic leukemia and basophilic leukocytosis.

BACKGROUND OF THE INVENTION

As a response to allergen exposure in allergic conditions, mast cells are activated and release mediators like histamine, thromboxane A2 (TxA2), cysteinyl leukotrienes (CysLTs) and prostaglandin D₂ (PGD₂). These mediators interact with their respective receptors and cause physiological effects such as increased vascular permeability, edema, pruritus, nasal and pulmonary congestion, bronchoconstriction, and mucus secretion. An increased vascular permeability for example, allows excessive infiltration of eosinophilic and basophilic leukocytes into the tissue and thus amplifies the allergic response.

Current treatments of allergic diseases comprise agents that can block or otherwise interrupt such interactions, e.g. anti-histamines (histamine H1 receptor antagonists), leukotriene receptor antagonists, beta-adrenergic receptor agonists, and corticosteroids. Generally, treatments with anti-histamines and leukotriene antagonists are limited in efficacy, and long-term usage of corticosteroids is often associated with unwanted side effects.

PGD₂ is an agonist known to act on two G-protein-coupled receptors, the PGD₂ receptor DP1 and the recently identified CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) receptor (also referred to as “DP2 receptor”).

Elevated PGD₂ levels are considered to cause inflammation as observed in allergic diseases such as allergic rhinitis, allergic asthma, allergic conjunctivitis, atopic dermatitis and the like. Therefore, blocking the interaction of PGD₂ with its receptors is considered a useful therapeutic strategy for the treatment of such diseases.

GB 2388540 discloses the use of ramatroban ((3R)-3-(4-fluorobenzene-sulfonamido)-1,2,3,4-tetrahydrocarbazole-9-propionic acid), a TxA2 receptor (also referred to as “TP receptor”) antagonist with additional antagonistic activity on CRTH2, for the prophylaxis and treatment of allergic diseases, such as asthma, allergic rhinitis or allergic conjunctivitis. In T. Ishizuka et al., Cardiovascular Drug Rev. 2004, 22(2), 71-90 effects of ramatroban on late-phase inflammation are described. Furthermore, oral bioavailability of ramatroban and its ability to inhibit prostaglandin D₂-induced eosinophil migration in vitro has been reported (Journal of Pharmacology and Experimental Therapeutics, 305(1), p. 347-352 (2003)).

WO 03/097598 and WO 03/097042 disclose Ramatroban analogues with CRTH2 antagonistic activity. Ulven et al, J. Med. Chem. 2005, 48(4), 897-900 disclose further ramatroban analogues.

CRTH2 antagonists containing a phenoxy-acetic acid moiety have been for instance described in WO 05/105727, WO 06/056752, WO 07/037,187 and WO 07/052,023.

DESCRIPTION OF THE INVENTION

1) The present invention relates to 1-phenyl-substituted heterocyclyl derivatives of the formula (I),

wherein X represents —NH—, —O— or a bond; Y represents (C₁-C₄)alkandiyl; Z represents O or S; n represents 0 or 1; R¹ represents

-   -   (C₄-C₆)alkyl;     -   (C₁-C₄)alkyl which is mono-substituted with (C₃-C₆)cycloalkyl,         (C₁-C₄)alkoxy, optionally substituted aryl, optionally         substituted heteroaryl, optionally substituted heterocyclyl,         optionally substituted aryloxy, optionally substituted         heteroaryloxy, optionally substituted aryl-(C₁-C₂)alkoxy,         optionally substituted heteroaryl-(C₁-C₂)alkoxy, optionally         substituted heteroarylsulfanyl or —NR⁸R⁹;     -   (C₂-C₄)alkenyl which is mono-substituted with optionally         substituted aryl;     -   (C₂-C₄)alkynyl which is mono-substituted with optionally         substituted aryl;     -   (C₃-C₆)cycloalkyl which is mono- or di-substituted with         (C₁-C₄)alkyl, mono-substituted with (C₁-C₄)alkoxy,         mono-substituted with optionally substituted aryl or         mono-substituted with optionally substituted heteroaryl;     -   optionally substituted aryl; or     -   a 10-membered partially unsaturated ring system;         R² represents hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,         (C₁-C₄)fluoroalkyl, halogen, (C₁-C₄)alkylsulfonyl,         phenylsulfonyl or (C₁-C₄)alkylsulfonylamino;         R³ represents hydrogen, (C₁-C₄)alkoxy or halogen;         R⁴ represents hydrogen, (C₁-C₄)alkoxy, halogen,         (C₁-C₄)alkylsulfonyl, optionally substituted aryl or optionally         substituted heteroaryl;         R⁵ represents hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,         (C₁-C₄)fluoroalkyl, halogen, cyano, —CONH₂, optionally         substituted aryl, optionally substituted heteroaryl,         (C₁-C₄)alkylsulfonyl, phenylsulfonyl or dimethylamino-sulfonyl;         and         R⁶ represents hydrogen or halogen; or         R⁵ and R⁶ together form a methylendioxy-group;         R⁷ represents hydrogen or methyl;         R⁸ represents hydrogen or methyl;         R⁹ represents optionally substituted aryl, optionally         substituted arylsulfonyl or optionally substituted         heteroarylsulfonyl; and         R¹⁰ represents —C(O)OH, —C(O)NH—CN, —C(O)NH—OH, —C(O)NH—S(O)₂CF₃         or optionally substituted heteroaryl;         with the proviso that R¹ is different from optionally         substituted aryl if X represents —NH— or a bond;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.

The compounds of formula (I) according to embodiment 1) may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms. Substituents at a double bond may be present in the (Z)- or (E)-configuration unless indicated otherwise. The compounds of formula (I) may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.

The following paragraphs provide definitions of the various chemical moieties for the compounds according to the invention and are intended to apply uniformly throughout the specification and claims unless an otherwise expressly set out definition provides a broader or narrower definition.

In this patent application, variably attached bonds may be used for substituents or groups. In such case it is meant that the substituent or group is attached to any carbon atom of the ring system to which the variable attached bond is drawn into, provided that said carbon atom is not already specifically substituted. For example, formula (I) encompasses the following three formulas:

For avoidance of any doubt, compounds of formula I wherein n represents 0 are represented by formula I_(ISO); and compounds of formula I wherein n represents 1 are represented by formula I_(TET):

The term “alkyl”, used alone or in combination, refers to a straight or branched chain alkyl group containing one to six carbon atoms. The term “(C_(x)-C_(y))alkyl” (x and y each being an integer), refers to an alkyl group as defined before containing x to y carbon atoms. For example a (C₁-C₄)alkyl group contains from one to four carbon atoms. Representative examples of (C₁-C₄)alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. Representative examples of (C₄-C₆)alkyl groups include n-butyl, iso-butyl, sec-butyl, tert-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 2-methyl-but-1-yl, 3-methyl-but-1-yl, 2-methyl-but-2-yl, 3-methyl-but-2-yl, 2,2-dimethyl-prop-1-yl and the isomeric hexyls. The alkyl group may be unsubstituted or substituted as explicitly defined.

In case “R¹” represents “(C₄-C₆)alkyl” the term means (C₄-C₆)alkyl groups as defined above. Examples of said groups are n-butyl, iso-butyl, sec-butyl, tert-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 2-methyl-but-1-yl, 3-methyl-but-1-yl, 2-methyl-but-2-yl, 3-methyl-but-2-yl, 2,2-dimethyl-prop-1-yl and the isomeric hexyls. Preferred are n-butyl, iso-butyl, tert-butyl, pent-1-yl, 2-methyl-but-1-yl, 3-methyl-but-1-yl and 2,2-dimethyl-prop-1-yl, more preferred are n-butyl, iso-butyl, tert-butyl and 2,2-dimethyl-prop-1-yl and most preferred are n-butyl, iso-butyl and 2,2-dimethyl-prop-1-yl.

In case “R¹” represents monosubstituted (C₁-C₄)alkyl the term “(C₁-C₄)alkyl” means (C₁-C₄)alkyl groups as defined above. Examples of said groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. Preferred are methyl, ethyl and n-propyl; most preferred are methyl and ethyl. The (C₁-C₄)alkyl groups are mono-substituted with (C₃-C₆)cycloalkyl, (C₁-C₄)alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted aryl-(C₁-C₂)alkoxy, optionally substituted heteroaryl-(C₁-C₂)alkoxy, optionally substituted heteroarylsulfanyl or —NR⁸R⁹ (and especially with optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryloxy, optionally substituted heteroaryloxy or optionally substituted aryl-(C₁-C₂)alkoxy).

In case “R¹” represents “(C₃-C₆)cycloalkyl which is mono- or di-substituted with (C₁-C₄)alkyl” the term “(C₁-C₄)alkyl” means (C₁-C₄)alkyl groups as defined above. Examples of said groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. Preferred are methyl, ethyl and isopropyl and most preferred is methyl.

In case “R²” represents “(C₁-C₄)alkyl” the term means (C₁-C₄)alkyl groups as defined above. Examples of said groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. Preferred is methyl.

In case “R⁵” represents “(C₁-C₄)alkyl” the term means (C₁-C₄)alkyl groups as defined above. Examples of said groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. Preferred are methyl and iso-propyl; most preferred is methyl.

In case “(C₁-C₄)alkyl” is a substituent to an aryl, a heteroaryl, a heterocyclyl, an aryloxy, a heteroaryloxy, an aryl-(C₁-C₂)alkoxy, a heteroaryl-(C₁-C₂)alkoxy, a heteroarylsulfanyl, an arylsulfonyl or a heteroarylsulfonyl group, the term “(C₁-C₄)alkyl” means (C₁-C₄)alkyl groups as defined above. Examples of said groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. Preferred are methyl and ethyl; most preferred is methyl.

The term “(C₁-C₄)alkandiyl” as used in Y refers to a carbon chain containing from one to four carbon atoms, which is attached to the oxygen-atom and to R¹⁰ as depicted in formula (I). The respective two residues may be attached to the same or to different carbon atoms of the alkandiyl group. Preferred examples of (C₁-C₄)alkandiyl groups are methandiyl, ethan-1,1-diyl, ethan-1,2-diyl, propan-1,3-diyl and butan-1,4-diyl. More preferred are methandiyl and ethan-1,1-diyl. Most preferred is methandiyl.

The term “alkenyl”, used alone or in combination, refers to a straight or branched chain alkenyl group containing two to four carbon atoms. The term “(C_(x)-C_(y))alkenyl” (x and y each being an integer), refers to an alkenyl group as defined before containing x to y carbon atoms. For example a (C₂-C₄)alkenyl group contains from two to four carbon atoms. Representative examples of (C₂-C₄)alkenyl groups include ethenyl, propenyl, 2-methyl-propenyl and butenyl. Preferred is ethenyl. The (C₂-C₄)alkenyl group is mono-substituted with optionally substituted aryl.

The term “alkynyl”, used alone or in combination, refers to a straight or branched chain alkynyl group containing two to four carbon atoms. The term “(C_(x)-C_(y))alkynyl” (x and y each being an integer), refers to an alkynyl group as defined before containing x to y carbon atoms. For example a (C₂-C₄)alkynyl group contains from two to four carbon atoms. Representative examples of (C₂-C₄)alkynyl groups include ethynyl, propynyl and butynyl. Preferred is ethynyl. The (C₂-C₄)alkynyl group is mono-substituted with optionally substituted aryl.

The term “alkoxy”, used alone or in combination, refers to an alkyl-O— group wherein the alkyl group is as defined before. The term “(C_(x)-C_(y))alkoxy” (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms. For example a (C₁-C₄)alkoxy group contains from one to four carbon atoms. Representative examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy.

In case “R¹” represents “(C₁-C₄)alkyl which is mono-substituted with (C₁-C₄)alkoxy” the term “(C₁-C₄)alkoxy” means (C₁-C₄)alkoxy groups as defined above. Examples of said groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Preferred are methoxy and iso-butoxy. Most preferred is methoxy.

In case “R¹” represents “(C₃-C₆)cycloalkyl which is mono-substituted with (C₁-C₄)alkoxy” the term “(C₁-C₄)alkoxy” means (C₁-C₄)alkoxy groups as defined above. Examples of said groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Preferred are methoxy and ethoxy. Most preferred is ethoxy.

In case “R²” represents “(C₁-C₄)alkoxy” the term means (C₁-C₄)alkoxy groups as defined above.

Examples of said groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Preferred is methoxy.

In case “R³” represents “(C₁-C₄)alkoxy” the term means (C₁-C₄)alkoxy groups as defined above. Examples of said groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Preferred is methoxy.

In case “R⁴” represents “(C₁-C₄)alkoxy” the term means (C₁-C₄)alkoxy groups as defined above. Examples of said groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Preferred is methoxy.

In case “R⁵” represents “(C₁-C₄)alkoxy” the term means (C₁-C₄)alkoxy groups as defined above. Examples of said groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Preferred is methoxy.

In case “(C₁-C₄)alkoxy” is a substituent to an aryl, a heteroaryl, a heterocyclyl, an aryloxy, a heteroaryloxy, an aryl-(C₁-C₂)alkoxy, a heteroaryl-(C₁-C₂)alkoxy, a heteroarylsulfanyl, an arylsulfonyl or a heteroarylsulfonyl group, the term “(C₁-C₄)alkoxy” means (C₁-C₄)alkoxy groups as defined above. Examples of said groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Preferred is methoxy.

The term “aryl-(C₁-C₂)alkoxy” refers to an (C₁-C₂)alkoxy group as defined above in which one hydrogen atom has been replaced with an aryl group as defined below. Examples of aryl-(C₁-C₂)alkoxy groups are aryl-methoxy, 1-aryl-ethoxy and 2-aryl-ethoxy. Preferred is aryl-methoxy.

The term “heteroaryl-(C₁-C₂)alkoxy” refers to an (C₁-C₂)alkoxy group as defined above in which one hydrogen atom has been replaced with a heteroaryl group as defined below. Examples of heteroaryl-(C₁-C₂)alkoxy groups are heteroaryl-methoxy, 1-heteroaryl-ethoxy and 2-heteroaryl-ethoxy. Preferred is heteroaryl-methoxy.

The term “(C₁-C₄)alkylsulfonyl”, used alone or in combination, refers to an alkyl-S(O)₂— group wherein the alkyl group is as defined before, which is attached to the rest of the molecule via the sulfur-atom. The term “(C_(x)-C_(y))alkylsulfonyl” (x and y each being an integer) refers to an alkylsulfonyl group as defined before containing x to y carbon atoms. For example a (C₁-C₄)alkylsulfonyl group contains from one to four carbon atoms. Representative examples of alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl, iso-butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl.

In case “R²” represents “(C₁-C₄)alkylsulfonyl” the term means (C₁-C₄)alkylsulfonyl groups as defined above. Examples of said groups are methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl, iso-butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl. Preferred are methylsulfonyl and ethylsulfonyl; most preferred is methylsulfonyl.

In case “R⁴” represents “(C₁-C₄)alkylsulfonyl” the term means (C₁-C₄)alkylsulfonyl groups as defined above. Examples of said groups are methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl, iso-butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl. Preferred are methylsulfonyl and ethylsulfonyl; most preferred is ethylsulfonyl.

In case “R⁵” represents “(C₁-C₄)alkylsulfonyl” the term means (C₁-C₄)alkylsulfonyl groups as defined above. Examples of said groups are methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl, iso-butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl. Preferred are methylsulfonyl and ethylsulfonyl; most preferred is ethylsulfonyl.

In case “(C₁-C₄)alkylsulfonyl” is a substituent to an aryl, a heteroaryl, a heterocyclyl, an aryloxy, a heteroaryloxy, an aryl-(C₁-C₂)alkoxy, a heteroaryl-(C₁-C₂)alkoxy, a heteroarylsulfanyl, an arylsulfonyl or a heteroarylsulfonyl group, the term “(C₁-C₄)alkylsulfonyl” means (C₁-C₄)alkylsulfonyl groups as defined above. Examples of said groups are methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl, iso-butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl. Preferred is methylsulfonyl.

The term “(C₁-C₄)alkylsulfonylamino”, used alone or in combination, refers to an alkyl-S(O)₂N-group wherein the alkyl group is as defined before, which is attached to the rest of the molecule via the nitrogen-atom. The term “(C_(x)-C_(y))alkylsulfonylamino” (x and y each being an integer) refers to an alkylsulfonylamino group as defined before containing x to y carbon atoms. For example a (C₁-C₄)alkylsulfonylamino group contains from one to four carbon atoms. Representative examples of alkylsulfonylamino groups include methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, iso-propylsulfonylamino, n-butylsulfonylamino, iso-butylsulfonylamino, sec-butylsulfonylamino and tert-butylsulfonyl-amino. Preferred is methylsulfonylamino.

The term “cycloalkyl”, used alone or in combination, refers to a cycloalkyl group containing three to six carbon atoms. The term “(C_(x)-C_(y))cycloalkyl” (x and y each being an integer), refers to a cycloalkyl group as defined before containing x to y carbon atoms. For example a (C₃-C₆)cycloalkyl group contains from three to six carbon atoms. A cycloalkyl group containing five or six carbon atoms may optionally be annelated to a benzene ring. Examples of (C₃-C₆)cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, indanyl, cyclohexyl and 1,2,3,4-tetrahydronaphthyl. The cycloalkyl group may be unsubstituted or substituted as explicitly defined.

In case “R¹” represents “(C₁-C₄)alkyl which is mono-substituted with (C₃-C₆)cycloalkyl” the term “(C₃-C₆)cycloalkyl” means (C₃-C₆)cycloalkyl groups as defined above. Examples of said groups are cyclopropyl, cyclobutyl, cyclopentyl, indanyl, cyclohexyl and 1,2,3,4-tetrahydronaphthyl. Preferred are cyclopropyl, indanyl and 1,2,3,4-tetrahydronaphthyl; most preferred is indanyl (especially indan-2-yl). In another embodiment cyclopentyl and cyclohexyl are preferred.

In case “R¹” represents “(C₃-C₆)cycloalkyl” the term means (C₃-C₆)cycloalkyl groups as defined above. Examples of said groups are cyclopropyl, cyclobutyl, cyclopentyl, indanyl, cyclohexyl and 1,2,3,4-tetrahydronaphthyl. Preferred are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; most preferred is cyclopropyl. The (C₃-C₆)cycloalkyl groups are mono- or di-substituted with (C₁-C₄)alkyl, mono-substituted with (C₁-C₄)alkoxy, mono-substituted with optionally substituted aryl or mono-substituted with optionally substituted heteroaryl (and preferably mono-substituted with optionally substituted aryl).

The term “(C_(x)-C_(y))fluoroalkyl” (x and y each being an integer) refers to an alkyl group as defined before containing x to y carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluoro. For example a (C₁-C₄)fluoroalkyl group contains from one to four carbon atoms in which one to nine hydrogen atoms have been replaced with fluoro.

In case “R²” represents “(C₁-C₄)fluoroalkyl” the term means a (C₁-C₄)fluoroalkyl group as defined above. Examples of said groups are difluoromethyl, trifluoromethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl. Preferred is trifluoromethyl.

In case “R⁵” represents “(C₁-C₄)fluoroalkyl” the term means a (C₁-C₄)fluoroalkyl group as defined above. Examples of said groups are difluoromethyl, trifluoromethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl. Preferred is trifluoromethyl.

In case “(C₁-C₄)fluoroalkyl” is a substituent to an aryl, a heteroaryl, a heterocyclyl, an aryloxy, a heteroaryloxy, an aryl-(C₁-C₂)alkoxy, a heteroaryl-(C₁-C₂)alkoxy, a heteroarylsulfanyl, an arylsulfonyl or a heteroarylsulfonyl group, the term “(C₁-C₄)fluoroalkyl” means (C₁-C₄)fluoroalkyl groups as defined above. Examples of said groups are difluoromethyl, trifluoromethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl. Preferred is trifluoromethyl.

The term halogen means fluoro, chloro, bromo or iodo.

In case “R²” represents “halogen” the term means preferably fluoro, chloro and bromo and most preferably fluoro.

In case “R³” represents “halogen” the term means preferably fluoro and chloro and most preferably fluoro.

In case “R⁴” represents “halogen” the term means preferably fluoro, chloro and bromo and most preferably fluoro.

In case “R⁵” represents “halogen” the term means preferably fluoro, chloro and bromo and most preferably fluoro and chloro.

In case “R⁶” represents “halogen” the term means preferably fluoro, chloro and bromo and most preferably fluoro.

In case “halogen” is a substituent to an aryl, a heteroaryl, a heterocyclyl, an aryloxy, a heteroaryloxy, an aryl-(C₁-C₂)alkoxy, a heteroaryl-(C₁-C₂)alkoxy, a heteroarylsulfanyl, an arylsulfonyl or a heteroarylsulfonyl group, the term means fluoro, chloro, bromo or iodo. Preferred examples are fluoro and chloro; most preferred is chloro.

The term “aryl”, used alone or in any combination, means a phenyl or a naphthyl group. Preferred is a phenyl group. An “optionally substituted aryl” group means an aryl group as defined before which is unsubstituted or substituted as explicitly defined.

In case R¹ represents “optionally substituted aryl” the term means the above-mentioned groups (preferably phenyl), which groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted or mono-substituted and most preferably mono-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl. Preferably the substituents are independently selected from the group consisting of halogen and (C₁-C₄)alkoxy. Examples of such optionally substituted aryl groups are phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 2-methoxy-phenyl and 4-methoxy-phenyl.

In case R¹ represents “(C₁-C₄)alkyl which is mono-substituted with optionally substituted aryl” the term “optionally substituted aryl” means the above-mentioned groups (preferably phenyl), which groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted, mono- or di-substituted and most preferably unsubstituted or mono-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)fluoroalkyl, (C₁-C₄)alkylsulfonyl, cyano, phenyl and 5-methyl-tetrazol-1-yl. Preferably the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)fluoroalkyl, (C₁-C₄)alkylsulfonyl, phenyl and 5-methyl-tetrazol-1-yl. More preferably the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl. In addition the term “optionally substituted aryl” may represent 2,3-dihydro-benzo[1,4]dioxinyl. Examples of such optionally substituted aryl groups are phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 2,3-dichloro-phenyl, 2,6-dichloro-phenyl, 2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl, 4-methylsulfonyl-phenyl, biphenyl-4-yl, 4-(5-methyl-tetrazol-1-yl)-phenyl and 2,3-dihydro-benzo[1,4]dioxin-6-yl (and especially phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 2,3-dichloro-phenyl, 2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 2-methoxy-phenyl, 3-methoxy-phenyl, 2-trifluoromethyl-phenyl and 3-trifluoromethyl-phenyl). Further examples of such optionally substituted aryl groups are naphthyl, 2,3-difluoro-phenyl, 2,4-difluoro-phenyl, 2,5-difluoro-phenyl, 2,6-difluoro-phenyl, 2,4-dichloro-phenyl, 2,5-dichloro-phenyl, 2-bromo-phenyl, 2-chloro-6-fluoro-phenyl, 2-chloro-5-fluoro-phenyl, 5-chloro-2-fluoro-phenyl, 2,3-dimethyl-phenyl, 2,4-dimethyl-phenyl, 2,6-dimethyl-phenyl, 2,4,6-trimethyl-phenyl, 2,3-dimethoxy-phenyl, 2,4-dimethoxy-phenyl, 2,6-dimethoxy-phenyl, 4-trifluoromethyl-phenyl, 2-cyano-phenyl (and especially 2,3-difluoro-phenyl, 2,4-difluoro-phenyl, 2,4-dichloro-phenyl, 2-chloro-6-fluoro-phenyl, 2,3-dimethyl-phenyl and 2,4-dimethyl-phenyl). In a preferred embodiment, in case X represents —NH—, the term “optionally substituted aryl” preferably means a phenyl group which is unsubstituted or mono-substituted, wherein the substituent is selected from halogen or (C₁-C₄)alkoxy (especially from fluoro, chloro or methoxy). In another preferred embodiment, in case X represents —O—, the term “optionally substituted aryl” preferably means a phenyl group which is unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted, mono- or di-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C_(r) C₄)fluoroalkyl and cyano (and preferably from fluoro, chloro, methyl, methoxy and trifluoromethyl). In still another preferred embodiment, in case X represents a bond, the term “optionally substituted aryl” means a phenyl or naphthyl group (preferably phenyl), which groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted, mono- or di-substituted and most preferably unsubstituted or mono-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)fluoroalkyl, (C₁-C₄)alkylsulfonyl, phenyl and 5-methyl-tetrazol-1-yl (and preferably from fluoro, chloro, methyl, methoxy and trifluoromethyl).

In case R¹ represents “(C₂-C₄)alkenyl which is mono-substituted with optionally substituted aryl” the term “optionally substituted aryl” means the above-mentioned groups (preferably phenyl), which groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted or mono-substituted and most preferably mono-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl. Preferably the substituents are independently selected from the group consisting of halogen and (C₁-C₄)alkyl. Examples of such optionally substituted aryl groups are 2-fluoro-phenyl and 2-methyl-phenyl.

In case R¹ represents “(C₂-C₄)alkynyl which is mono-substituted with optionally substituted aryl” the term “optionally substituted aryl” means the above-mentioned groups (preferably phenyl), which groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted or mono-substituted and most preferably unsubstituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl. An example of such an optionally substituted aryl group is phenyl.

In case R¹ represents “(C₃-C₆)cycloalkyl which is mono-substituted with optionally substituted aryl” the term “optionally substituted aryl” means the above-mentioned groups (preferably phenyl), which groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted, mono- or di-substituted and most preferably unsubstituted or mono-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl. Examples of such optionally substituted aryl groups are phenyl, 2-fluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 2,4-dichloro-phenyl, 2-methyl-phenyl, 2-methoxy-phenyl and 2-trifluoromethyl-phenyl. Further examples of such optionally substituted aryl groups are 3-fluoro-phenyl, 4-fluoro-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 3-trifluoromethyl-phenyl and 4-trifluoromethyl-phenyl.

In case R⁴ represents “optionally substituted aryl” the term means the above-mentioned groups (preferably phenyl), which groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted or mono-substituted and most preferably mono-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl. Preferably the substituents are independently selected from the group consisting of halogen. An example of such an optionally substituted aryl group is 4-fluoro-phenyl.

In case R⁵ represents “optionally substituted aryl” the term means the above-mentioned groups (preferably phenyl), which groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted or mono-substituted and most preferably mono-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl. Preferably the substituents are independently selected from the group consisting of halogen. An example of such an optionally substituted aryl group is 4-fluoro-phenyl.

In case R⁹ represents “optionally substituted aryl” the term means the above-mentioned groups (preferably phenyl), which groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted or mono-substituted and most preferably unsubstituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl. An example of such an optionally substituted aryl group is phenyl.

The term “aryloxy”, used alone or in combination, refers to an aryl-O— group wherein the aryl group is as defined before. An “optionally substituted aryloxy” group means an aryloxy group as defined before which is unsubstituted or substituted as explicitly defined.

In case R¹ represents “(C₁-C₄)alkyl which is mono-substituted with optionally substituted aryloxy” the term “optionally substituted aryloxy” means the above-mentioned groups (preferably phenoxy), which groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted or mono-substituted and most preferably mono-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)fluoroalkyl and phenyl. Preferably the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl and most preferably from halogen and (C₁-C₄)alkyl. Examples of such optionally substituted aryloxy groups are phenoxy, 2-fluoro-phenoxy, 3-fluoro-phenoxy, 4-fluoro-phenoxy, 2-chloro-phenoxy, 3-chloro-phenoxy, 4-chloro-phenoxy, 2-methyl-phenoxy, 3-methyl-phenoxy, 4-methyl-phenoxy and biphenyl-2-yl. Further examples of such optionally substituted aryloxy groups are 2,4-dimethyl-phenoxy, 2-methoxy-phenoxy and 4-methoxy-phenoxy.

The term “optionally substituted aryl-(C₁-C₂)alkoxy”, used alone or in combination, refers to an aryl-(C₁-C₂)alkoxy group as defined above wherein the aryl group is unsubstituted or substituted as explicitly defined.

In case R¹ represents “(C₁-C₄)alkyl which is mono-substituted with optionally substituted aryl-(C₁-C₂)alkoxy” the term “optionally substituted aryl-(C₁-C₂)alkoxy” means the above-mentioned groups, wherein the term “aryl” means a phenyl or a naphthyl group (preferably a phenyl group). The aryl groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted or mono-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C_(r) C₄)fluoroalkyl. Preferably the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl and (C₁-C₄)alkoxy. Examples of such aryl groups are phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 2-methoxy-phenyl, 3-methoxy-phenyl and 4-methoxy-phenyl.

The term “arylsulfonyl”, used alone or in combination, refers to an aryl-S(O)₂— group wherein the aryl group is as defined before, which is attached to the rest of the molecule via the sulfur-atom. An “optionally substituted arylsulfonyl” group means an arylsulfonyl group as defined before which is unsubstituted or substituted as explicitly defined.

In case R⁹ represents “optionally substituted arylsulfonyl” the term means the above-mentioned groups (preferably phenylsulfonyl), which groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted, mono- or di-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)fluoroalkyl. Preferably the substituents are independently selected from the group consisting of halogen (especially fluoro). Examples of such optionally substituted arylsulfonyl groups are phenylsulfonyl, 2-fluoro-phenylsulfonyl, 3-fluoro-phenylsulfonyl and 3,4-difluoro-phenylsulfonyl.

The term “heteroaryl”, used alone or in combination, means a 5- to 10-membered monocyclic or bicyclic aromatic ring containing 1, 2, 3 or 4 heteroatoms (preferably 1, 2 or 3 heteroatoms, more preferably 1 or 2 heteroatoms) independently selected from oxygen, nitrogen and sulfur. Examples of such heteroaryl groups are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzo[2,1,3]oxadiazolyl, benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl and phthalazinyl. Further examples are tetrazolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, 5H-pyrrolo[2,3-b]pyrazinyl and imidazo[4,5-b]pyridinyl. Preferred examples of such heteroaryl groups are isoxazolyl (notably isoxazol-3-yl, isoxazol-4-yl and isoxazol-5-yl), oxadiazolyl (notably [1,2,4]oxadiazol-3-yl and [1,3,4]oxadiazol-2-yl), thiazolyl (notably thiazol-2-yl, thiazol-4-yl and thiazol-5-yl), imidazolyl (notably imidazol-2-yl and imidazol-4-yl), pyrazolyl (notably pyrazol-1-yl and pyrazol-3-yl), triazolyl (notably [1,2,3]triazol-1-yl, [1,2,3]triazol-2-yl and [1,2,3]triazol-4-yl), tetrazolyl (notably tetrazol-5-yl), pyridyl (notably pyridin-2-yl, pyridin-3-yl and pyridin-4-yl), pyrimidyl (notably pyrimidin-4-yl and pyrimidin-5-yl), pyrazinyl (notably pyrazin-2-yl), indolyl (notably indol-1-yl, indol-2-yl and indol-3-yl), benzofuranyl (notably benzofuran-3-yl), benzothiophenyl (notably benzothiophen-3-yl), indazolyl (notably indazol-1-yl indazol-2-yl and indazol-3-yl), benzimidazolyl (notably benzimidazol-1-yl and benzimidazol-2-yl), benzoxazolyl (notably benzoxazol-2-yl)benzisoxazolyl (notably benzisoxazol-3-yl), benzothiazolyl (notably benzothiazol-2-yl), pyrrolo[2,3-b]pyridinyl (notably pyrrolo[2,3-b]pyridin-1-yl), pyrrolo[2,3-c]pyridinyl (notably pyrrolo[2,3-c]pyridin-1-yl), pyrrolo[3,2-b]pyridinyl (notably pyrrolo[3,2-b]pyridin-1-yl), pyrrolo[3,2-c]pyridinyl (notably pyrrolo[3,2-c]pyridin-1-yl), 5H-pyrrolo[2,3-b]pyrazinyl (notably 5H-pyrrolo[2,3-b]pyrazin-5-yl), imidazo[4,5-b]pyridinyl (notably imidazo[4,5-b]pyridin-6-yl) and quinolinyl (notably quinolin-6-yl, quinolin-7-yl and quinolin-8-yl). More preferred examples of such heteroaryl groups are isoxazolyl (notably isoxazol-4-yl), oxadiazolyl (notably [1,2,4]oxadiazol-3-yl), thiazolyl (notably thiazol-4-yl), imidazolyl (notably imidazol-2-yl and imidazol-4-yl), pyrazolyl (notably pyrazol-3-yl), triazolyl (notably [1,2,3]triazol-1-yl, [1,2,3]triazol-2-yl and [1,2,3]triazol-4-yl), pyridyl (notably pyridin-3-yl), pyrimidyl (notably pyrimidin-5-yl), indolyl (notably indol-1-yl, indol-2-yl and indol-3-yl), benzofuranyl (notably benzofuran-3-yl), benzothiophenyl (notably benzothiophen-3-yl), indazolyl (notably indazol-2-yl), benzimidazolyl (notably benzimidazol-1-yl and benzimidazol-2-yl), benzisoxazolyl (notably benzisoxazol-3-yl), benzothiazolyl (notably benzothiazol-2-yl) and quinolinyl (notably quinolin-6-yl and quinolin-7-yl). An “optionally substituted heteroaryl” group means an heteroaryl group as defined before which is unsubstituted or substituted as explicitly defined.

In case R¹ represents “(C₁-C₄)alkyl which is mono-substituted with optionally substituted heteroaryl” the term “heteroaryl” means the above-mentioned groups. Preferred examples of such heteroaryl groups are isoxazolyl (notably isoxazol-3-yl, isoxazol-4-yl and isoxazol-5-yl), thiazolyl (notably thiazol-2-yl, thiazol-4-yl and thiazol-5-yl), imidazolyl (notably imidazol-2-yl and imidazol-4-yl), pyrazolyl (notably pyrazol-1-yl and pyrazol-3-yl), triazolyl (notably [1,2,3]triazol-4-yl), pyridyl (notably pyridin-2-yl and pyridin-3-yl), pyrimidyl (notably pyrimidin-4-yl and pyrimidin-5-yl), pyrazinyl (notably pyrazin-2-yl), indolyl (notably indol-1-yl, indol-2-yl and indol-3-yl), benzofuranyl (notably benzofuran-3-yl), benzothiophenyl (notably benzothiophen-3-yl), indazolyl (notably indazol-1-yl, indazol-2-yl and indazol-3-yl), benzimidazolyl (notably benzimidazol-1-yl and benzimidazol-2-yl), benzoxazolyl (notably benzoxazol-2-yl), benzisoxazolyl (notably benzisoxazol-3-yl), benzothiazolyl (notably benzothiazol-2-yl), pyrrolo[2,3-b]pyridinyl (notably pyrrolo[2,3-b]pyridin-1-yl), pyrrolo[2,3-c]pyridinyl (notably pyrrolo[2,3-c]pyridin-1-yl), pyrrolo[3,2-b]pyridinyl (notably pyrrolo[3,2-b]pyridin-1-yl), pyrrolo[3,2-c]pyridinyl (notably pyrrolo[3,2-c]pyridin-1-yl), 5H-pyrrolo[2,3-b]pyrazinyl (notably 5H-pyrrolo[2,3-b]pyrazin-5-yl) and quinolinyl (notably quinolin-6-yl and quinolin-7-yl). More preferred examples of such heteroaryl groups are thiazolyl (notably thiazol-4-yl), imidazolyl (notably imidazol-2-yl and imidazol-4-yl), triazolyl (notably [1,2,3]triazol-4-yl), indolyl (notably indol-1-yl, indol-2-yl and indol-3-yl), benzofuranyl (notably benzofuran-3-yl), benzothiophenyl (notably benzothiophen-3-yl), indazolyl (notably indazol-2-yl), benzimidazolyl (notably benzimidazol-1-yl and benzimidazol-2-yl), benzisoxazolyl (notably benzisoxazol-3-yl), benzothiazolyl (notably benzothiazol-2-yl) and quinolinyl (notably quinolin-6-yl and quinolin-7-yl). Most preferred are imidazolyl (notably imidazol-4-yl), indolyl (notably indol-3-yl), benzofuranyl (notably benzofuran-3-yl), benzisoxazolyl (notably benzisoxazol-3-yl) and quinolinyl (notably quinolin-6-yl). Preferred examples, in case X represents —O—, are isoxazolyl (notably isoxazol-3-yl, isoxazol-4-yl and isoxazol-5-yl), thiazolyl (notably thiazol-2-yl, thiazol-4-yl and thiazol-5-yl), imidazolyl (notably imidazol-4-yl), pyrazolyl (notably pyrazol-1-yl and pyrazol-3-yl), pyridyl (notably pyridin-3-yl), pyrimidyl (notably pyrimidin-4-yl and pyrimidin-5-yl), pyrazinyl (notably pyrazin-2-yl), indazolyl (notably indazol-1-yl and indazol-3-yl), benzimidazolyl (notably benzimidazol-1-yl), benzoxazolyl (notably benzoxazol-2-yl) and benzisoxazolyl (notably benzisoxazol-3-yl). Preferred examples, in case X represents a bond, are thiazolyl (notably thiazol-4-yl), imidazolyl (notably imidazol-2-yl and imidazol-4-yl), triazolyl (notably [1,2,3]triazol-4-yl), pyridyl (notably pyridin-2-yl and pyridin-3-yl), indolyl (notably indol-1-yl, indol-2-yl and indol-3-yl), benzofuranyl (notably benzofuran-3-yl), benzothiophenyl (notably benzothiophen-3-yl), indazolyl (notably indazol-1-yl and indazol-2-yl), benzimidazolyl (notably benzimidazol-1-yl and benzimidazol-2-yl), benzisoxazolyl (notably benzisoxazol-3-yl), benzothiazolyl (notably benzothiazol-2-yl), pyrrolo[2,3-b]pyridinyl (notably pyrrolo[2,3-b]pyridin-1-yl), pyrrolo[2,3-c]pyridinyl (notably pyrrolo[2,3-c]pyridin-1-yl), pyrrolo[3,2-b]pyridinyl (notably pyrrolo[3,2-b]pyridin-1-yl), pyrrolo[3,2-c]pyridinyl (notably pyrrolo[3,2-c]pyridin-1-yl), 5H-pyrrolo[2,3-b]pyrazinyl (notably 5H-pyrrolo[2,3-b]pyrazin-5-yl) and quinolinyl (notably quinolin-6-yl and quinolin-7-yl); most preferred, in case X represents a bond, are imidazolyl (notably imidazol-4-yl), indolyl (notably indol-1-yl and indol-3-yl), benzofuranyl (notably benzofuran-3-yl), indazolyl (notably indazol-1-yl), benzisoxazolyl (notably benzisoxazol-3-yl) and pyrrolo[2,3-b]pyridinyl (notably pyrrolo[2,3-b]pyridin-1-yl). The heteroaryl groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted, mono- or di-substituted and most preferably unsubstituted or mono-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, trifluoromethyl, cyano and phenyl, wherein the phenyl is unsubstituted or mono- or di-substituted with methyl. Preferably the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and phenyl, wherein the phenyl is unsubstituted or mono- or di-substituted with methyl. Most preferably the substituents are independently selected from the group consisting of (C₁-C₄)alkyl and (C₁-C₄)alkoxy. Examples of such optionally substituted heteroaryl groups are 2-methyl-thiazol-4-yl, 1-phenyl-imidazol-2-yl, 3-(2,3-dimethyl-phenyl)-imidazol-4-yl (preferred), 3-phenyl-[1,2,3]triazol-4-yl, indol-1-yl, 5-methoxy-indol-2-yl, indol-3-yl, 5-fluoro-indol-3-yl, 5-chloro-indol-3-yl, 1-methyl-indol-3-yl (preferred), 2-methyl-indol-3-yl (preferred), 1-ethyl-2-methyl-indol-3-yl, 5-methoxy-indol-3-yl (preferred), 6-methoxy-benzofuran-3-yl, benzothiophen-3-yl, 5-chloro-benzothiophen-3-yl, indazol-2-yl, benzimidazol-1-yl, benzimidazol-2-yl, benzisoxazol-3-yl, 5-methyl-benzisoxazol-3-yl, 5-methoxy-benzisoxazol-3-yl (preferred), benzothiazol-2-yl, quinolin-6-yl and quinolin-7-yl. Further examples are 4-methyl-isoxazol-3-yl, 5-methyl-isoxazol-3-yl, 3,5-dimethyl-isoxazol-4-yl, 3-methyl-isoxazol-5-yl, thiazol-2-yl, 4-methyl-thiazol-2-yl, 5-methyl-thiazol-2-yl, 2-methyl-thiazol-5-yl, 4-methyl-thiazol-5-yl, 4-methyl-pyrazol-1-yl, 3,5-dimethyl-pyrazol-1-yl, 2-methyl-pyrazol-3-yl, 2,5-dimethyl-pyrazol-3-yl, 2-ethyl-5-methyl-pyrazol-3-yl, 1,5-dimethyl-pyrazol-3-yl, 3-methyl-imidazol-4-yl, 2,6-dimethyl-pyridin-3-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, 3-methyl-indol-1-yl, 6-methyl-indol-1-yl, 6-methoxy-indol-1-yl, 4,6-dimethoxy-indol-1-yl, 6-chloro-indol-1-yl, 2-trifluoromethyl-indol-1-yl, indazol-1-yl, 4-fluoro-indazol-1-yl, 5-fluoro-indazol-1-yl, 6-fluoro-indazol-1-yl, 7-fluoro-indazol-1-yl, 4-fluoro-3-methyl-indazol-1-yl, 6-fluoro-3-methyl-indazol-1-yl, 7-fluoro-3-methyl-indazol-1-yl, 4-chloro-indazol-1-yl, 5-chloro-indazol-1-yl, 6-chloro-indazol-1-yl, 7-chloro-indazol-1-yl, 4-chloro-3-methyl-indazol-1-yl, 6-chloro-3-methyl-indazol-1-yl, 3-methyl-indazol-1-yl, 1-methyl-indazol-3-yl, 3-chloro-indazol-1-yl, benzoxazol-2-yl, 3-chloro-5H-pyrrolo[2,3-b]pyrazin-5-yl, and 6-methoxy-pyrrolo[2,3-b]pyridin-1-yl.

In case R¹ represents “(C₃-C₆)cycloalkyl which is mono-substituted with optionally substituted heteroaryl” the term “heteroaryl” means the above-mentioned groups. Preferred are 5- or 6-membered monocyclic heteroaryl groups containing 1, 2 or 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from oxygen, nitrogen and sulfur. Examples of such 5- or 6-membered monocyclic heteroaryl groups are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl. A preferred example of such a heteroaryl group is thiazolyl (notably thiazol-5-yl). The heteroaryl groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted, mono- or di-substituted and most preferably di-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and trifluoromethyl. Most preferably the substituents are selected from (C₁-C₄)alkyl. An example of such an optionally substituted heteroaryl group is 2,4-dimethyl-thiazol-5-yl.

In case R⁴ represents “optionally substituted heteroaryl” the term “heteroaryl” means the above-mentioned groups. Preferred are 5- or 6-membered monocyclic heteroaryl groups containing 1, 2 or 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from oxygen, nitrogen and sulfur. Examples of such 5- or 6-membered monocyclic heteroaryl groups are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl. A preferred example of such a heteroaryl group is pyrimidyl (notably pyrimidin-5-yl). The heteroaryl groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted, mono- or di-substituted and most preferably unsubstituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl and (C₁-C₄)alkoxy. Most preferably the substituents are selected from (C₁-C₄)alkyl. An example of such an optionally substituted heteroaryl group is pyrimidin-5-yl.

In case R⁵ represents “optionally substituted heteroaryl” the term “heteroaryl” means the above-mentioned groups. Preferred are 5- or 6-membered monocyclic heteroaryl groups containing 1, 2 or 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from oxygen, nitrogen and sulfur. Examples of such 5- or 6-membered monocyclic heteroaryl groups are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl. Preferred examples of such heteroaryl groups are oxadiazolyl (notably [1,2,4]oxadiazol-3-yl), triazolyl (notably [1,2,3]triazol-1-yl and [1,2,3]triazol-2-yl) and pyrimidyl (notably pyrimidin-5-yl). The heteroaryl groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted or mono-substituted and most preferably unsubstituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and mercapto (preferred). Examples of such optionally substituted heteroaryl groups are 5-mercapto-[1,2,4]oxadiazol-3-yl (tautomer to 5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl), [1,2,3]triazol-1-yl (preferred), [1,2,3]triazol-2-yl (preferred) and pyrimidin-5-yl.

In case R¹⁰ represents “optionally substituted heteroaryl” the term “heteroaryl” means the above-mentioned groups. Preferred are 5- or 6-membered monocyclic heteroaryl groups containing 1, 2, 3 or 4 heteroatoms (preferably 2, 3 or 4 heteroatoms) independently selected from oxygen, nitrogen and sulfur. Examples of such 5- or 6-membered monocyclic heteroaryl groups are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl. Preferred examples of such heteroaryl groups are isoxazolyl (notably isoxazol-5-yl), oxadiazolyl (notably [1,2,4]oxadiazol-3-yl and [1,3,4]oxadiazol-2-yl) and tetrazolyl (notably tetrazol-5-yl). The heteroaryl groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted or mono-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and hydroxy (preferred). Examples of such optionally substituted heteroaryl groups are 3-hydroxy-isoxazol-5-yl (tautomer to isoxazol-3(2H)-on-5-yl), 5-hydroxy-[1,2,4]oxadiazol-3-yl (tautomer to 1,2,4-oxadiazol-5(4H)-on-3-yl), 5-hydroxy-[1,3,4]oxadiazol-2-yl (tautomer to 1,3,4-oxadiazol-5(4H)-on-2-yl) and tetrazol-5-yl.

The term “heteroaryloxy”, used alone or in combination, refers to an heteroaryl-O— group wherein the heteroaryl group is as defined before. An “optionally substituted heteroaryloxy” group means a heteroaryloxy group as defined before which is unsubstituted or substituted as explicitly defined.

In case R¹ represents “(C₁-C₄)alkyl which is mono-substituted with optionally substituted heteroaryloxy” the term “optionally substituted heteroaryloxy” means the above-mentioned groups. Preferred are 5- or 6-membered monocyclic heteroaryloxy groups containing in the heteroaryl moiety 1, 2 or 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from oxygen, nitrogen and sulfur. Examples of such 5- or 6-membered monocyclic heteroaryloxy groups are furanyloxy, oxazolyloxy, isoxazolyloxy, oxadiazolyloxy, thienyloxy, thiazolyloxy, isothiazolyloxy, thiadiazolyloxy, pyrrolyloxy, imidazolyloxy, pyrazolyloxy, triazolyloxy, pyridyloxy, pyrimidyloxy, pyridazinyloxy and pyrazinyloxy. A preferred example of such heteroaryloxy group is pyridyloxy (notably pyridin-3-yloxy). Further preferred examples are imidazo[4,5-b]pyridinyloxy (notably imidazo[4,5-b]pyridin-6-yloxy) and quinolinyloxy (notably quinolin-8-yloxy). The heteroaryloxy groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted, mono- or di-substituted and most preferably di-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, 2-hydroxy-ethoxy, cyano, —C(O)NH₂ and trifluoromethyl (preferably from halogen, (C₁-C₄)alkyl and (C₁-C₄)alkoxy and most preferably from (C₁-C₄)alkyl). An example of such an optionally substituted heteroaryloxy group is 2,6-dimethyl-pyridin-3-yloxy. Further examples are pyridin-3-yloxy, 2-fluoro-pyridin-3-yloxy, 5-fluoro-pyridin-3-yloxy, 2-chloro-pyridin-3-yloxy, 4-chloro-pyridin-3-yloxy, 5-chloro-pyridin-3-yloxy, 6-chloro-pyridin-3-yloxy, 2-methyl-pyridin-3-yloxy, 5-methyl-pyridin-3-yloxy, 6-methyl-pyridin-3-yloxy, 5-methyl-2-methoxy-pyridin-3-yloxy, 5-methoxy-pyridin-3-yloxy, 6-methoxy-pyridin-3-yloxy, 2,6-dimethoxy-pyridin-3-yloxy, 5,6-dimethoxy-pyridin-3-yloxy, 2-(2-hydroxy-ethoxy)-pyridin-3-yloxy, 2-cyano-pyridin-3-yloxy, 2-carbamoyl-pyridin-3-yloxy, 6-trifluoromethyl-pyridin-3-yloxy, 2,6-dichloro-pyridin-4-yloxy, 3-methyl-imidazo[4,5-b]pyridin-6-yloxy and quinolin-8-yloxy.

The term “heteroarylsulfanyl”, used alone or in combination, refers to a heteroaryl-S— group wherein the heteroaryl group is as defined before. An “optionally substituted heteroarylsulfanyl” group means a heteroarylsulfanyl group as defined before which is unsubstituted or substituted as explicitly defined.

In case R¹ represents “(C₁-C₄)alkyl which is mono-substituted with optionally substituted heteroarylsulfanyl” the term “optionally substituted heteroarylsulfanyl” means the above-mentioned groups. Preferred are 5- or 6-membered monocyclic heteroarylsulfanyl groups containing in the heteroaryl moiety 1, 2 or 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from oxygen, nitrogen and sulfur. Examples of such 5- or 6-membered monocyclic heteroarylsulfanyl groups are furanylsulfanyl, oxazolylsulfanyl, isoxazolylsulfanyl, oxadiazolylsulfanyl, thienylsulfanyl, thiazolylsulfanyl, isothiazolylsulfanyl, thiadiazolylsulfanyl, pyrrolylsulfanyl, imidazolylsulfanyl, pyrazolylsulfanyl, triazolylsulfanyl, pyridylsulfanyl, pyrimidylsulfanyl, pyridazinylsulfanyl and pyrazinylsulfanyl. A preferred example of such a heteroarylsulfanyl group is triazolylsulfanyl (notably [1,2,3]triazol-4-ylsulfanyl). The heteroarylsulfanyl groups are independently unsubstituted, mono-, di- or tri-substituted (preferably mono-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and phenyl (and preferably from phenyl). An example of such an optionally substituted heteroarylsulfanyl group is 3-phenyl-3H-[1,2,3]triazol-4-ylsulfanyl.

The term “heteroarylsulfonyl”, used alone or in combination, refers to a heteroaryl-S(O)₂— group wherein the heteroaryl group is as defined before, which is attached to the rest of the molecule via the sulfur-atom. An “optionally substituted heteroarylsulfonyl” group means a heteroarylsulfonyl group as defined before which is unsubstituted or substituted as explicitly defined.

In case R⁹ represents “optionally substituted heteroarylsulfonyl” the term means the above-mentioned groups. Preferred are 5- or 6-membered monocyclic heteroarylsulfonyl groups containing in the heteroaryl moiety 1, 2 or 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from oxygen, nitrogen and sulfur. Examples of such 5- or 6-membered monocyclic heteroarylsulfonyl groups are furanylsulfonyl, oxazolylsulfonyl, isoxazolylsulfonyl, oxadiazolylsulfonyl, thienylsulfonyl, thiazolylsulfonyl, isothiazolylsulfonyl, thiadiazolylsulfonyl, pyrrolylsulfonyl, imidazolylsulfonyl, pyrazolylsulfonyl, triazolylsulfonyl, pyridylsulfonyl, pyrimidylsulfonyl, pyridazinylsulfonyl and pyrazinylsulfonyl. A preferred example of such a heteroarylsulfonyl group is isoxazolylsulfonyl (notably isoxazole-4-sulfonyl). The heteroarylsulfonyl groups are independently unsubstituted, mono-, di- or tri-substituted (preferably di-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl and (C₁-C₄)alkoxy (and preferably from (C₁-C₄)alkyl). An example of such an optionally substituted heteroarylsulfonyl group is 3,5-dimethyl-isoxazole-4-sulfonyl.

The term “optionally substituted heteroaryl-(C₁-C₂)alkoxy”, used alone or in combination, refers to an heteroaryl-(C₁-C₂)alkoxy group as defined above wherein the heteroaryl group is unsubstituted or substituted as explicitly defined.

In case R¹ represents “(C₁-C₄)alkyl which is mono-substituted with optionally substituted heteroaryl-(C₁-C₂)alkoxy” the term “optionally substituted heteroaryl-(C₁-C₂)alkoxy” means the above-mentioned groups, wherein the term “heteroaryl” means a heteroaryl group as defined above and preferably a 5- or 6-membered monocyclic heteroaryl group containing 1, 2 or 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from oxygen, nitrogen and sulfur. Examples of such 5- or 6-membered monocyclic heteroaryl groups as used in “optionally substituted heteroaryl-(C₁-C₂)alkoxy” are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl. A preferred example of such a heteroaryl group is pyrazolyl (notably pyrazol-3-yl). The heteroaryl groups as used in “optionally substituted heteroaryl-(C₁-C₂)alkoxy” are independently unsubstituted, mono-, di- or tri-substituted (preferably mono-substituted), wherein the substituents are independently selected from the group consisting of halogen, (C₁-C₄)alkyl and (C₁-C₄)alkoxy (and preferably from (C₁-C₄)alkyl). An example of such an optionally substituted heteroaryl group as used in “optionally substituted heteroaryl-(C₁-C₂)alkoxy” is 1-methyl-1H-pyrazol-3-yl. A preferred example of an optionally substituted heteroaryl-(C₁-C₂)alkoxy group is 1-methyl-1H-pyrazol-3-ylmethoxy.

The term “heterocyclyl”, used alone or in combination, refers to a saturated monocyclic moiety of 5 to 7 ring members containing 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, it being understood that a heterocyclyl group does not contain 2 sulfur atoms. The sulfur atom of a heterocyclyl group may be in an oxidised form, i.e. as a sulfoxide or sulfonyl. A heterocyclyl group may optionally be annealed to a benzene ring. An “optionally substituted heterocyclyl” group means a heterocyclyl group as defined before which is unsubstituted or substituted as explicitly defined.

In case R¹ represents “(C₁-C₄)alkyl which is mono-substituted with optionally substituted heterocyclyl” the term “heterocyclyl” means the above-mentioned groups. Examples of such heterocyclyl groups are pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, indolinyl, isoindolinyl, dihydrobenzofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, chromanyl, dihydrobenzooxazinyl, dihydrobenzothiazinyl and dihydrobenzodioxinyl. Preferred examples are thiazolidinyl (notably thiazolidin-3-yl), indolinyl (notably indolin-1-yl), isoindolinyl (notably isoindolin-2-yl), tetrahydroquinolinyl (notably 1,2,3,4-tetrahydroquinolin-1-yl) and dihydrobenzooxazinyl (notably 2,3-dihydro-benzo[1,4]oxazin-4-yl). A further preferred example is pyrrolidinyl (notably pyrrolidin-1-yl). The heterocyclyl groups are independently unsubstituted, mono-, di- or tri-substituted (preferably unsubstituted, mono- or di-substituted), wherein the substituents are independently selected from the group consisting of halogen, oxo and phenyl. Examples of such optionally substituted heterocyclyl groups are 4-oxo-2-phenyl-thiazolidin-3-yl, indolin-1-yl, isoindolin-2-yl, 1,2,3,4-tetrahydroquinolin-1-yl and 6-chloro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl. Further examples are 2-oxo-pyrrolidin-1-yl, 4-methyl-2-oxo-thiazolidin-3-yl, 2-oxo-thiazolidin-3-yl and 1-oxo-isoindolin-2-yl.

The term “10-membered partially unsaturated ring system”, means a tetrahydronaphthyl (notably 1,2,3,4-tetrahydronaphth-2-yl) or a chromenyl (notably 2H-chromen-3-yl) group.

2) A further embodiment of the invention relates to compounds of formula (I) according to embodiment 1) that are also compounds of formula (I_(P)),

wherein X represents —NH—, —O— or a bond; Y represents (C₁-C₄)alkandiyl; Z represents O or S; R¹ represents

-   -   (C₄-C₆)alkyl;     -   (C₁-C₄)alkyl which is mono-substituted with (C₃-C₆)cycloalkyl,         (C₁-C₄)alkoxy, optionally substituted aryl, optionally         substituted heteroaryl, optionally substituted heterocyclyl,         optionally substituted aryloxy, optionally substituted         heteroaryloxy, optionally substituted aryl-(C₁-C₂)alkoxy,         optionally substituted heteroaryl-(C₁-C₂)alkoxy, optionally         substituted heteroarylsulfanyl or —NR⁸R⁶;     -   (C₂-C₄)alkenyl which is mono-substituted with optionally         substituted aryl;     -   (C₂-C₄)alkynyl which is mono-substituted with optionally         substituted aryl;     -   (C₃-C₆)cycloalkyl which is mono-substituted with optionally         substituted aryl;     -   optionally substituted aryl; or     -   a 10-membered partially unsaturated ring system;         R² represents hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,         (C₁-C₄)fluoroalkyl, halogen, (C₁-C₄)alkylsulfonyl,         phenylsulfonyl or (C₁-C₄)alkylsulfonylamino;         R³ represents hydrogen, (C₁-C₄)alkoxy or halogen;         R⁴ represents hydrogen, (C₁-C₄)alkoxy, halogen or         (C₁-C₄)alkylsulfonyl;         R⁵ represents hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,         (C₁-C₄)fluoroalkyl, halogen, cyano, —CONH₂, optionally         substituted aryl, optionally substituted heteroaryl,         (C₁-C₄)alkylsulfonyl, phenylsulfonyl or dimethylamino-sulfonyl;         R⁶ represents hydrogen or halogen; or         R⁵ and R⁶ together form a methylendioxy-group;         R⁷ represents hydrogen or methyl;         R⁸ represents hydrogen or methyl; and         R⁹ represents optionally substituted arylsulfonyl or optionally         substituted heteroarylsulfonyl; with the proviso that     -   (1) R¹ is different from optionally substituted aryl if X         represents —NH— or a bond; and     -   (2) at least one of R⁵ and R⁶ is different from hydrogen;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         3) A further embodiment of the invention relates to compounds         according to embodiment 1), wherein         X represents —NH—, —O— or a bond;         Y represents (C₁-C₄)alkandiyl;         Z represents O;         n represents 0 or 1;         R¹ represents     -   (C₁-C₄)alkyl which is mono-substituted with (C₃-C₆)cycloalkyl,         (C₁-C₄)alkoxy, optionally substituted aryl, optionally         substituted heteroaryl, optionally substituted heterocyclyl,         optionally substituted aryloxy, optionally substituted         heteroaryloxy, optionally substituted aryl-(C₁-C₂)alkoxy,         optionally substituted heteroaryl-(C₁-C₂)alkoxy or optionally         substituted heteroarylsulfanyl;     -   (C₃-C₆)cycloalkyl which is mono- or di-substituted with         (C₁-C₄)alkyl, mono-substituted with (C₁-C₄)alkoxy,         mono-substituted with optionally substituted aryl or         mono-substituted with optionally substituted heteroaryl;         R² represents hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,         (C₁-C₄)fluoroalkyl, halogen or (C₁-C₄)alkylsulfonyl;         R³ represents hydrogen, (C₁-C₄)alkoxy or halogen;         R⁴ represents hydrogen, (C₁-C₄)alkoxy or halogen;         R⁵ represents hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,         (C₁-C₄)fluoroalkyl, halogen, cyano, optionally substituted aryl,         optionally substituted heteroaryl or phenylsulfonyl;         R⁶ represents hydrogen or halogen; or         R⁷ represents hydrogen; and         R¹⁰ represents —C(O)OH, —C(O)NH—CN, —C(O)NH—OH, —C(O)NH—S(O)₂CF         or optionally substituted heteroaryl;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         4) A further embodiment of the invention relates to compounds         according to embodiment 1) or 2), wherein         X represents —NH—, —O— or a bond;         Y represents (C₁-C₄)alkandiyl;         Z represents O;         R¹ represents     -   (C₁-C₄)alkyl which is mono-substituted with (C₃-C₆)cycloalkyl,         (C₁-C₄)alkoxy, optionally substituted aryl, optionally         substituted heteroaryl, optionally substituted heterocyclyl,         optionally substituted aryloxy, optionally substituted         heteroaryloxy, optionally substituted aryl-(C₁-C₂)alkoxy,         optionally substituted heteroaryl-(C₁-C₂)alkoxy or optionally         substituted heteroarylsulfanyl; or     -   (C₃-C₆)cycloalkyl which is mono-substituted with optionally         substituted aryl;         R² represents hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,         (C₁-C₄)fluoroalkyl, halogen or (C₁-C₄)alkylsulfonyl;         R³ represents hydrogen, (C₁-C₄)alkoxy or halogen;         R⁴ represents hydrogen, (C₁-C₄)alkoxy or halogen;         R⁵ represents (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)fluoroalkyl,         halogen, cyano, optionally substituted aryl, optionally         substituted heteroaryl or phenylsulfonyl;         R⁶ represents hydrogen or halogen; and         R⁷ represents hydrogen or methyl; and to the salts (in         particular pharmaceutically acceptable salts) of such compounds.         5) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 4), wherein         X represents —NH—, —O— or a bond;         Y represents (C₁-C₄)alkandiyl;         Z represents O;         R¹ represents     -   (C₁-C₄)alkyl which is mono-substituted with optionally         substituted aryl, optionally substituted heteroaryl, optionally         substituted aryloxy, optionally substituted heteroaryloxy or         optionally substituted aryl-(C₁-C₂)alkoxy; or     -   cyclopropyl which is mono-substituted with optionally         substituted aryl;         R² represents hydrogen, methyl, methoxy, trifluoromethyl or         halogen;         R³ represents hydrogen or fluoro;         R⁴ represents hydrogen, methoxy or fluoro;         R⁵ represents trifluoromethyl, halogen, cyano, optionally         substituted aryl or optionally substituted heteroaryl;         R⁶ represents hydrogen or fluoro; and         R⁷ represents hydrogen; and to the salts (in particular         pharmaceutically acceptable salts) of such compounds.         6) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 5), wherein         X represents —O— or a bond;         Y represents methandiyl;         Z represents O;         n represents 0 or 1;

R¹ represents

-   -   (C₁-C₂)alkyl which is mono-substituted with optionally         substituted aryl, optionally substituted heteroaryl or         optionally substituted aryl-(C₁-C₂)alkoxy (preferably with         optionally substituted aryl or optionally substituted         heteroaryl); or     -   cyclopropyl which is mono-substituted with optionally         substituted aryl;         R² represents hydrogen, trifluoromethyl or fluoro (preferably         hydrogen or fluoro);         R³ represents hydrogen or fluoro;         R⁴ represents hydrogen;         R⁵ represents halogen or cyano (preferably chloro);         R⁶ represents hydrogen;         R⁷ represents hydrogen; and         R¹⁰ represents —C(O)OH;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         7) A further embodiment of the invention relates to compounds         according to embodiment 1) or 2), wherein         X represents —NH—;         Y represents (C₁-C₄)alkandiyl (preferably methandiyl);         Z represents O or S;         R¹ represents (C₁-C₄)alkyl (preferably methyl or ethyl) which is         mono-substituted with phenyl, which phenyl is unsubstituted or         mono-substituted with halogen or (C₁-C₄)alkoxy (and preferably         with chloro or methoxy);         R² represents hydrogen;         R³ represents hydrogen;         R⁴ represents hydrogen;         R⁵ represents halogen (preferably fluoro or chloro);         R⁶ represents hydrogen;         R⁷ represents hydrogen;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         8) A further embodiment of the invention relates to compounds         according to embodiment 1) or 2), wherein         X represents —O—;         Y represents (C₁-C₄)alkandiyl;         Z represents O;         R¹ represents     -   (C₄-C₆)alkyl;     -   (C₁-C₄)alkyl which is mono-substituted with (C₁-C₄)alkoxy or         optionally substituted aryl; or     -   optionally substituted aryl;         R² represents hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,         (C₁-C₄)fluoroalkyl, halogen, (C₁-C₄)alkylsulfonyl,         phenylsulfonyl or (C₁-C₄)alkylsulfonylamino;         R³ represents hydrogen, (C₁-C₄)alkoxy or halogen;         R⁴ represents hydrogen, (C₁-C₄)alkoxy, halogen or         (C₁-C₄)alkylsulfonyl;         R⁵ represents hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,         (C₁-C₄)fluoroalkyl, halogen, cyano, —CONH₂, optionally         substituted aryl, optionally substituted heteroaryl,         (C₁-C₄)alkylsulfonyl, phenylsulfonyl or dimethylamino-sulfonyl;         R⁶ represents hydrogen or halogen; or         R⁵ and R⁶ together form a methylendioxy-group;         R⁷ represents hydrogen or methyl;         with the proviso that at least one of R⁵ and R⁶ is different         from hydrogen;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         9) A further embodiment of the invention relates to compounds         according to any one of embodiments 1), 2) or 8), wherein         X represents —O—;         Y represents (C₁-C₄)alkandiyl;         Z represents O;         R¹ represents (C₁-C₄)alkyl which is mono-substituted with         optionally substituted aryl;         R² represents hydrogen, methyl, methoxy, trifluoromethyl or         halogen;         R³ represents hydrogen, methoxy or fluoro;         R⁴ represents hydrogen, methoxy or fluoro;         R⁵ represents trifluoromethyl, halogen, cyano, optionally         substituted aryl or optionally substituted heteroaryl;         R⁶ represents hydrogen or fluoro;         R⁷ represents hydrogen; and to the salts (in particular         pharmaceutically acceptable salts) of such compounds.         10) A further embodiment of the invention relates to compounds         according to embodiment 1), wherein         X represents —O—;         Y represents (C₁-C₂)alkandiyl (preferably methandiyl);         Z represents O;         n represents 0 or 1;         R¹ represents (C₁-C₂)alkyl which is mono-substituted with         (C₃-C₆)cycloalkyl, (C₁-C₄)alkoxy, optionally substituted aryl or         optionally substituted heteroaryl (preferably with optionally         substituted aryl or optionally substituted heteroaryl);         R² represents hydrogen, methyl, methoxy, trifluoromethyl or         halogen (preferably hydrogen, trifluoromethyl or fluoro);         R³ represents hydrogen or halogen (preferably hydrogen or         fluoro);         R⁴ represents hydrogen, (C₁-C₄)alkoxy or halogen (preferably         hydrogen or fluoro);         R⁵ represents halogen, cyano, optionally substituted aryl or         optionally substituted heteroaryl (preferably fluoro, chloro or         cyano);         R⁶ represents hydrogen;         R⁷ represents hydrogen; and         R¹⁰ represents —C(O)OH, —C(O)NH—S(O)₂CF or optionally         substituted heteroaryl (preferably —C(O)OH);         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         11) A further embodiment of the invention relates to compounds         according to embodiment 1) or 2), wherein         X represents a bond;         Y represents (C₁-C₄)alkandiyl;         Z represents O;         R¹ represents     -   (C₁-C₄)alkyl which is mono-substituted with (C₃-C₆)cycloalkyl,         (C₁-C₄)alkoxy, optionally substituted aryl, optionally         substituted heteroaryl, optionally substituted heterocyclyl,         optionally substituted aryloxy, optionally substituted         heteroaryloxy, optionally substituted aryl-(C₁-C₂)alkoxy,         optionally substituted heteroaryl-(C₁-C₂)alkoxy, optionally         substituted heteroarylsulfanyl or —NR⁸R⁹;     -   (C₂-C₄)alkenyl which is mono-substituted with optionally         substituted aryl;     -   (C₂-C₄)alkynyl which is mono-substituted with optionally         substituted aryl; or     -   (C₃-C₆)cycloalkyl which is mono-substituted with optionally         substituted aryl;         R² represents hydrogen or halogen;         R³ represents hydrogen;         R⁴ represents hydrogen;         R⁵ represents halogen or cyano;         R⁶ represents hydrogen;         R⁷ represents hydrogen;         R⁸ represents hydrogen or methyl; and         R⁹ represents optionally substituted arylsulfonyl or optionally         substituted heteroarylsulfonyl;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         12) A further embodiment of the invention relates to compounds         according to embodiment 1), wherein         X represents a bond;         Y represents methandiyl;         Z represents O;         n represents 0 or 1;         R¹ represents     -   (C₁-C₄)alkyl (preferably (C₁-C₃)alkyl) which is mono-substituted         with (C₃-C₆)cycloalkyl, optionally substituted aryl, optionally         substituted heteroaryl, optionally substituted heterocyclyl,         optionally substituted aryloxy, optionally substituted         heteroaryloxy or optionally substituted aryl-(C₁-C₂)alkoxy         (preferably with optionally substituted aryl, optionally         substituted heteroaryl, optionally substituted aryloxy or         optionally substituted aryl-(C₁-C₂)alkoxy);     -   cyclopropyl which is di-substituted with methyl,         mono-substituted with optionally substituted aryl or         mono-substituted with optionally substituted heteroaryl         (preferably mono-substituted with optionally substituted aryl);         R² represents hydrogen or halogen (preferably hydrogen or         fluoro);         R³ represents hydrogen or halogen (preferably hydrogen or         fluoro);         R⁴ represents hydrogen;         R⁵ represents halogen or cyano (preferably fluoro or chloro);         R⁶ represents hydrogen;         R⁷ represents hydrogen; and         R¹⁰ represents —C(O)OH;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         13) A further embodiment of the invention relates to compounds         according to any one of embodiments 1), 2) 11) or 12), wherein         X represents a bond;         Y represents methandiyl;         Z represents O;         R¹ represents     -   (C₁-C₄)alkyl which is mono-substituted with optionally         substituted aryl, optionally substituted heteroaryl, optionally         substituted aryloxy, optionally substituted heteroaryloxy or         optionally substituted aryl-(C₁-C₂)alkoxy; or     -   cyclopropyl which is mono-substituted with optionally         substituted aryl;         R² represents hydrogen or fluoro;         R³ represents hydrogen;         R⁴ represents hydrogen;         R⁵ represents fluoro, chloro or cyano;         R⁶ represents hydrogen;         R⁷ represents hydrogen;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         14) A further embodiment of the invention relates to compounds         according to embodiment 1), wherein         X represents —NH—, —O— or a bond;         Y represents methandiyl;         Z represents O;         n represents 0;         R¹ represents     -   (C₁-C₄)alkyl (preferably (C₁-C₂)alkyl) which is mono-substituted         with optionally substituted aryl, optionally substituted         heteroaryl, optionally substituted heterocyclyl, optionally         substituted aryloxy, optionally substituted heteroaryloxy or         optionally substituted aryl-(C₁-C₂)alkoxy;     -   cyclopropyl which is mono-substituted with optionally         substituted aryl;         R² represents hydrogen or halogen (preferably hydrogen or         fluoro);         R³ represents hydrogen or halogen (preferably hydrogen or         fluoro);         R⁴ represents hydrogen;         R⁵ represents halogen (preferably fluoro or chloro);         R⁶ represents hydrogen;         R⁷ represents hydrogen;         R¹⁰ represents —C(O)OH;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         15) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 5), 7) or 14), wherein         X represents —NH—;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         16) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 6), 8) to 10) or 14),         wherein         X represents —O—;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         17) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 6) or 11) to 14),         wherein         X represents a bond;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         18) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 5), 7) to 11) or 15)         to 17), wherein         Y represents methandiyl, ethan-1,1-diyl or propan-1,3-diyl (and         preferably methandiyl or ethan-1,1-diyl);         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         19) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 11) or 15) to 17),         wherein         Y represents methandiyl or (R)-configured ethan-1,1-diyl (and         preferably methandiyl); and to the salts (in particular         pharmaceutically acceptable salts) of such compounds.         20) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 19), wherein         Z represents O;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         21) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) or 3) to 20), wherein         n represents 0;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         22) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 20), wherein         n represents 1;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         23) A further embodiment of the invention relates to compounds         according to any one of embodiments 1), 2), 8) or 15) to 22),         wherein         R¹ represents (C₄-C₆)alkyl;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         24) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) or 15) to 22), wherein         R¹ represents     -   (C₁-C₄)alkyl (preferably (C₁-C₂)alkyl) which is mono-substituted         with (C₃-C₆)cycloalkyl, (C₁-C₄)alkoxy, optionally substituted         aryl, optionally substituted heteroaryl, optionally substituted         heterocyclyl, optionally substituted aryloxy, optionally         substituted heteroaryloxy, optionally substituted         aryl-(C₁-C₂)alkoxy, optionally substituted         heteroaryl-(C₁-C₂)alkoxy, optionally substituted         heteroarylsulfanyl or —NR⁸R⁹; or     -   (C₃-C₆)cycloalkyl (preferably cyclopropyl) which is mono- or         di-substituted with (C₁-C₄)alkyl, mono-substituted with         (C₁-C₄)alkoxy, mono-substituted with optionally substituted aryl         or mono-substituted with optionally substituted heteroaryl;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         25) A further embodiment of the invention relates to compounds         according to any one of embodiments 1), 3) or 15) to 22),         wherein         R¹ represents     -   (C₁-C₄)alkyl (preferably (C₁-C₃)alkyl) which is mono-substituted         with (C₃-C₆)cycloalkyl, optionally substituted aryl, optionally         substituted heteroaryl, optionally substituted heterocyclyl,         optionally substituted aryloxy, optionally substituted         heteroaryloxy, optionally substituted aryl-(C₁-C₂)alkoxy or         optionally substituted heteroaryl-(C₁-C₂)alkoxy; or     -   cyclopropyl which is mono- or di-substituted with (C₁-C₄)alkyl,         mono-substituted with optionally substituted aryl or         mono-substituted with optionally substituted heteroaryl         (preferably mono- or di-substituted with (C₁-C₄)alkyl or         mono-substituted with optionally substituted aryl and most         preferably mono-substituted with optionally substituted aryl);         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         26) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 4), 11) or 15) to 22),         wherein         R¹ represents     -   (C₁-C₄)alkyl which is mono-substituted with (C₃-C₆)cycloalkyl,         (C₁-C₄)alkoxy, optionally substituted aryl, optionally         substituted heteroaryl, optionally substituted heterocyclyl,         optionally substituted aryloxy, optionally substituted         heteroaryloxy, optionally substituted aryl-(C₁-C₂)alkoxy,         optionally substituted heteroaryl-(C₁-C₂)alkoxy or optionally         substituted heteroarylsulfanyl; or     -   (C₃-C₆)cycloalkyl which is mono-substituted with optionally         substituted aryl; and to the salts (in particular         pharmaceutically acceptable salts) of such compounds.         27) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 5) or 11) to 22),         wherein         R¹ represents     -   (C₁-C₄)alkyl which is mono-substituted with optionally         substituted aryl, optionally substituted heteroaryl, optionally         substituted aryloxy, optionally substituted heteroaryloxy or         optionally substituted aryl-(C₁-C₂)alkoxy; or     -   cyclopropyl which is mono-substituted with optionally         substituted aryl; and to the salts (in particular         pharmaceutically acceptable salts) of such compounds.         28) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 5) or 11) to 22),         wherein         R¹ represents (C₁-C₄)alkyl which is mono-substituted with         optionally substituted aryl, optionally substituted heteroaryl,         optionally substituted aryloxy, optionally substituted         heteroaryloxy or optionally substituted aryl-(C₁-C₂)alkoxy (and         preferably with optionally substituted aryl or optionally         substituted heteroaryl); and to the salts (in particular         pharmaceutically acceptable salts) of such compounds.         29) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 6) or 10) to 28),         wherein         the substituent for a (C₁-C₄)alkyl group, a (C₁-C₃)alkyl group         or a (C₁-C₂)alkyl group, if representing R¹, is selected from         optionally substituted aryl or optionally substituted         heteroaryl; and to the salts (in particular pharmaceutically         acceptable salts) of such compounds.         30) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 22) or 24) to 29),         wherein the mono-substituted (C₁-C₄)alkyl group, if representing         R¹, is selected from methyl; ethyl substituted in 2-position;         and n-propyl substituted in 3-position;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         31) A further embodiment of the invention relates to compounds         according to any one of embodiments 1), 3) or 15) to 22),         wherein         R¹ represents (C₃-C₆)cycloalkyl (preferably cyclopropyl) which         is mono- or di-substituted with (C₁-C₄)alkyl, mono-substituted         with (C₁-C₄)alkoxy, mono-substituted with optionally substituted         aryl or mono-substituted with optionally substituted heteroaryl;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         32) A further embodiment of the invention relates to compounds         according to any one of embodiments 1), 3), 12) or 15) to 22),         wherein         R¹ represents (C₃-C₆)cycloalkyl (preferably cyclopropyl) which         is mono-substituted with optionally substituted aryl or         mono-substituted with optionally substituted heteroaryl; and to         the salts (in particular pharmaceutically acceptable salts) of         such compounds.         33) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 6) or 11) to 22),         wherein         R¹ represents (C₃-C₆)cycloalkyl (preferably cyclopropyl) which         is mono-substituted with optionally substituted aryl;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         34) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 5), 8) to 10) or 15)         to 33), wherein         R² represents hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,         (C₁-C₄)fluoroalkyl or halogen (and preferably hydrogen, methyl,         methoxy, trifluoromethyl, fluoro, chloro or bromo);         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         35) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 6), 8) to 10) or 15)         to 33), wherein         R² represents hydrogen, (C₁-C₄)fluoroalkyl or halogen (and         preferably hydrogen, trifluoromethyl or fluoro);         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         36) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 6) or 8) to 33),         wherein         R² represents halogen (and preferably fluoro); and to the salts         (in particular pharmaceutically acceptable salts) of such         compounds.         37) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 33), wherein         R² represents hydrogen;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         38) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 6), 8) to 10), 12)         or 14) to 37), wherein         R³ represents hydrogen or halogen (and preferably hydrogen or         fluoro); and to the salts (in particular pharmaceutically         acceptable salts) of such compounds.         39) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 37), wherein         R³ represents hydrogen;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         40) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 5), 8) to 10) or 15)         to 39), wherein         R⁴ represents hydrogen, (C₁-C₄)alkoxy or halogen (and preferably         hydrogen, methoxy or fluoro); and to the salts (in particular         pharmaceutically acceptable salts) of such compounds.         41) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 5), 8) to 10) or 15)         to 39), wherein         R⁴ represents hydrogen or halogen (and preferably hydrogen or         fluoro); and to the salts (in particular pharmaceutically         acceptable salts) of such compounds.         42) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 39), wherein         R⁴ represents hydrogen;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         43) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 4), 8) or 15) to 42),         wherein         R⁵ represents (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)fluoroalkyl,         halogen, cyano, optionally substituted aryl, optionally         substituted heteroaryl or phenylsulfonyl;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         44) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 5), 8), 9) or 15) to         42), wherein         R⁵ represents (C₁-C₄)fluoroalkyl, halogen, cyano, optionally         substituted aryl or optionally substituted heteroaryl (and         preferably trifluoromethyl, fluoro, chloro, bromo, cyano,         4-fluorophenyl, [1,2,3]triazol-1-yl or [1,2,3]triazol-2-yl);         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         45) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 6), 8) to 13) or 15)         to 42), wherein         R⁵ represents halogen or cyano (and preferably fluoro, chloro or         cyano); and to the salts (in particular pharmaceutically         acceptable salts) of such compounds.         46) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 42), wherein         R⁵ represents halogen (and preferably fluoro or chloro); and to         the salts (in particular pharmaceutically acceptable salts) of         such compounds.         47) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 5), 8) to 10) or 15)         to 42), wherein         R⁵ represents optionally substituted aryl or optionally         substituted heteroaryl (and preferably 4-fluorophenyl,         [1,2,3]triazol-1-yl or [1,2,3]triazol-2-yl);         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         48) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 47), wherein         at least one of R⁵ and R⁶ is different from hydrogen;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         49) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 3), 8) or 15) to 42),         wherein         R⁵ represents hydrogen; and         R⁶ represents halogen (preferably fluoro);         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         50) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 48), wherein         R⁶ represents hydrogen;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         51) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 50), wherein         R⁷ represents hydrogen;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         52) A further embodiment of the invention relates to compounds         according to any one of embodiments 1), 3) to 5), 7) to 11), 13)         or 15) to 51), wherein         R¹⁰ represents —C(O)OH, —C(O)NH—S(O)₂CF₃ or optionally         substituted heteroaryl;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         53) A further embodiment of the invention relates to compounds         according to any one of embodiments 1), 3) to 5), 7) to 11), 13)         or 15) to 51), wherein         R¹⁰ represents —C(O)OH or optionally substituted heteroaryl;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         54) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 51), wherein         R¹⁰ represents —C(O)OH;         and to the salts (in particular pharmaceutically acceptable         salts) of such compounds.         55) A further embodiment of the invention relates to compounds         according to any one of embodiments 1) to 54), wherein the         absolute configuration of the stereogenic center is as depicted         in formula (I_(St1))

and to the salts (in particular pharmaceutically acceptable salts) of such compounds. 56) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 54), wherein the absolute configuration of the stereogenic center is as depicted in formula (I_(St2))

and to the salts (in particular pharmaceutically acceptable salts) of such compounds. 57) Preferred compounds of formula (I) as defined in embodiment 1) are selected from the group consisting of:

-   1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-[2-((S)-1-Carboxy-ethoxy)-5-fluoro-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-methyl-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(5-Bromo-2-carboxymethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   7-Bromo-1-(2-carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-4,5-difluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   5-Bromo-1-(2-carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-[2-((R)-1-Carboxy-ethoxy)-5-fluoro-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-fluoro-phenyl)-6,7-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(5-Bromo-2-carboxymethoxy-phenyl)-6,7-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-cyano-phenyl)-6,7-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-fluoro-phenyl)-5-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-[2-((R)-1-Carboxy-ethoxy)-5-cyano-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-fluoro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-cyano-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-dimethylsulfamoyl-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-cyano-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-trifluoromethyl-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-isopropyl-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(6-Carboxymethoxy-benzo[1,3]dioxol-5-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-methoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   (S)-1-(2-Carboxymethoxy-5-cyano-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   (S)-1-[2-((R)-1-Carboxy-ethoxy)-5-fluoro-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   (S)-1-[2-((S)-1-Carboxy-ethoxy)-5-fluoro-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   {4-Fluoro-2-[(S)-2-((trans)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   (S)-1-(2-Carboxymethoxy-5-cyano-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-3,5-difluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-fluoro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-fluoro-phenyl)-5-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-fluoro-phenyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-fluoro-phenyl)-7-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-fluoro-phenyl)-5-chloro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-fluoro-phenyl)-5-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   5-Bromo-1-(2-carboxymethoxy-5-fluoro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-fluoro-phenyl)-7-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-fluoro-phenyl)-5,7-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-5,7-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-cyano-phenyl)-5,7-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   {2-[2-(2-Benzo[d]isoxazol-3-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic     acid; -   {4-Fluoro-2-[2-(3-methyl-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   {4-Fluoro-2-[2-(2-naphthalen-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   {4-Fluoro-2-[2-(2-quinolin-7-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   {4-Fluoro-2-[2-(2-quinolin-6-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   {2-[2-(2-2,3-Dihydro-benzo[1,4]dioxin-6-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic     acid; -   {4-Fluoro-2-[2-(3-1H-indol-3-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   (2-{2-[3-(1-Ethyl-2-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic     acid; -   (2-{2-[3-(2,6-Dichloro-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic     acid; -   (4-Fluoro-2-{2-[3-(2-fluoro-phenoxy)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   [4-Fluoro-2-(2-{2-[4-(5-methyl-tetrazol-1-yl)-phenyl]acetyl}-1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic     acid; -   (2-{2-[3-(6-Chloro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic     acid; -   (4-Fluoro-2-{2-[2-(2-methyl-thiazol-4-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   {2-[2-(2-Benzo[b]thiophen-3-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic     acid; -   {2-[2-(3-Benzothiazol-2-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic     acid; -   {2-[2-(2-Biphenyl-4-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic     acid; -   {4-Fluoro-2-[2-(2-indol-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   {2-[2-(2-1H-Benzoimidazol-2-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic     acid; -   {2-[2-(2-1,3-Dihydro-isoindol-2-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic     acid; -   (4-Fluoro-2-{2-[3-(5-methoxy-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Fluoro-2-{2-[3-(2-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Fluoro-2-{2-[3-(1-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   {4-Fluoro-2-[2-(trans-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   {4-Chloro-2-[2-(2-cyclopropyl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   {4-Chloro-2-[2-(2H-chromene-3-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   {4-Chloro-2-[2-(3-methoxy-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   (4-Chloro-2-{2-[2-(2-chloro-phenyl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   {4-Chloro-2-[2-(2-indol-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   (4-Chloro-2-{2-[3-(2-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(5-methoxy-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[2-(2,6-dimethyl-pyridin-3-yloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(1-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   {4-Chloro-2-[2-(1,2,3,4-tetrahydro-naphthalene-2-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   {2-[2-(2-Benzoimidazol-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-chloro-phenoxy}-acetic     acid; -   {4-Chloro-2-[2-(2-3,4-dihydro-2H-quinolin-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   {4-Chloro-2-[2-(2-indazol-2-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   (4-Chloro-2-{2-[3-(3-trifluoromethyl-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-trans-[2-(2-chloro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(1-phenyl-1H-imidazol-2-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(4-oxo-2-phenyl-thiazolidin-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   [4-Chloro-2-(2-{3-[3-(2,3-dimethyl-phenyl)-3H-imidazol-4-yl]-propionyl}-1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic     acid; -   (2-{2-[2-(Biphenyl-2-yloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-chloro-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(3-fluoro-phenoxy)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   {4-Chloro-2-[2-(3-p-tolyloxy-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   (4-Chloro-2-{2-[3-(4-chloro-phenoxy)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(2-trifluoromethyl-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[2-(5-fluoro-1H-indol-3-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[2-(6-methoxy-benzofuran-3-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[4-(4-chloro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   {4-Chloro-2-[2-(3-m-tolyloxy-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   (4-Chloro-2-{2-[3-(3-chloro-phenoxy)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[2-(5-chloro-1H-indol-3-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   {4-Chloro-2-[2-(4-p-tolyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   (4-Chloro-2-{2-[2-(5-chloro-benzo[b]thiophen-3-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[2-(5-methoxy-1H-indol-2-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[2-(5-methyl-benzo[d]isoxazol-3-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[2-(5-methoxy-benzo[d]isoxazol-3-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(4-fluoro-phenoxy)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[4-(4-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   {4-Chloro-2-[2-(3-o-tolyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   {2-[2-(2-Benzyloxy-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-chloro-phenoxy}-acetic     acid; -   (4-Chloro-2-{2-[2-(2-chloro-benzyloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   {4-Chloro-2-[2-(4-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   (4-Chloro-2-{2-[4-(3-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[4-(2,3-dichloro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   {4-Chloro-2-[2-(4-m-tolyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   {4-Chloro-2-[2-(4-o-tolyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   (4-Chloro-2-{2-[4-(3-chloro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[4-(2-chloro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[4-(3-methoxy-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[4-(2-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   {4-Chloro-2-[2-(trans-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   {4-Chloro-2-[5-fluoro-2-(trans-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   {4-Chloro-2-[5-fluoro-2-(3-o-tolyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   {2-[2-(2-Benzyloxy-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-chloro-phenoxy}-acetic     acid; -   (4-Chloro-2-{2-[2-(2-chloro-benzyloxy)-acetyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   {4-Chloro-2-[5-fluoro-2-(4-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   {4-Chloro-2-[5-fluoro-2-(3-phenyl-propynoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   {4-Fluoro-2-[2-(3-phenyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   [4-Fluoro-2-(2-phenylacetyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic     acid; -   {4-Fluoro-2-[2-(2-phenoxy-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   {2-[2-(2-Benzyloxy-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic     acid; -   {4-Fluoro-2-[2-(4-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   (4-Fluoro-2-{2-[3-(2-methoxy-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Fluoro-2-{2-[3-(3-methoxy-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Fluoro-2-{2-[3-(4-methoxy-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (2-{2-[3-(2-Chloro-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic     acid; -   (2-{2-[3-(3-Chloro-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic     acid; -   (2-{2-[3-(4-Chloro-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic     acid; -   {4-Fluoro-2-[2-(3-o-tolyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   {4-Fluoro-2-[2-(2-naphthalen-2-yl-acetyl)     1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; -   {4-Fluoro-2-[2-(2-o-tolyloxy-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   (4-Fluoro-2-{2-[2-(1-methyl-1H-indol-3-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (2-{2-[2-(2-Chloro-phenoxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic     acid; -   (4-Fluoro-2-{2-[3-(2-fluoro-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   {4-Fluoro-2-[2-(2-indan-2-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   (4-Fluoro-2-{2-[(E)-3-(2-fluoro-phenyl)-acryloyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   {4-Fluoro-2-[2-((E)-3-o-tolyl-acryloyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   {4-Fluoro-2-[2-(5-phenyl-pentanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   {4-Fluoro-2-[2-(3-phenoxy-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   (4-Fluoro-2-{2-[3-(4-methanesulfonyl-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   {2-[2-(3-2,3-Dihydro-indol-1-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic     acid; -   {4-Fluoro-2-[2-(3-o-tolyloxy-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   (4-Fluoro-2-{2-[2-(2-fluoro-phenoxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Fluoro-2-{2-[4-(2-methoxy-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (2-{2-[2-(2-Chloro-benzyloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[(trans)-2-(3-chloro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   {4-Chloro-2-[2-((trans)-2-o-tolyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   (4-Chloro-2-{2-[(trans)-2-(2-trifluoromethyl-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[trans-2-(4-chloro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[trans-2-(2,4-dichloro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[trans-2-(2-methoxy-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[trans-2-(2-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(3-phenyl-3H-[1,2,3]triazol-4-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[2-(3-phenyl-3H-[1,2,3]triazol-4-ylsulfanyl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   1-(2-Carboxymethoxy-5-fluoro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-chloro-benzyl ester; -   1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-chloro-benzyl ester; -   1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2,2-dimethyl-propyl ester; -   1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid butyl ester; -   1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-methoxy-phenyl ester; -   1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid phenyl ester; -   1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-chloro-phenyl ester; -   1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid isobutyl ester; -   1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-methoxy-ethyl ester; -   1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 4-methoxy-phenyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-chloro-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-chloro-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-(2-chloro-phenyl)-ethyl ester; -   1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-(2-chloro-phenyl)-ethyl ester; -   1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3-chloro-phenyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-(2-chloro-phenyl)-ethyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-fluoro-phenyl)-7-ethanesulfonyl-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-methanesulfonyl-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(5-Benzenesulfonyl-2-carboxymethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-ethanesulfonyl-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-fluoro-phenyl)-5-methanesulfonyl-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-fluoro-phenyl)-5-ethanesulfonyl-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   5-Benzenesulfonyl-1-(2-carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-pyrimidin-5-yl-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(4-Carboxymethoxy-4′-fluoro-biphenyl-3-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   (2-{2-[2-(3-Chloro-benzyloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic     acid; -   (2-{2-[2-(4-Chloro-benzyloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic     acid; -   (4-Fluoro-2-{2-[2-(2-methyl-benzyloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Fluoro-2-{2-[2-(3-methyl-benzyloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Fluoro-2-{2-[2-(4-methyl-benzyloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Fluoro-2-{2-[2-(3-methoxy-benzyloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Fluoro-2-{2-[2-(4-methoxy-benzyloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Fluoro-2-{2-[2-(1-methyl-1H-pyrazol-3-ylmethoxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Fluoro-2-{2-[2-(2-methoxy-benzyloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   [2-(2-Benzylcarbamoyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-4-fluoro-phenoxy]-acetic     acid; -   [4-Fluoro-2-(2-phenethylcarbamoyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic     acid; -   {4-Fluoro-2-[2-(2-methoxy-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   {4-Chloro-2-[2-(2-methoxy-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   {2-[2-(2-Chloro-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic     acid; -   (2-{2-[2-(2-Chloro-phenyl)-ethylcarbamoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic     acid; -   {2-[2-(2-Benzenesulfonylamino-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic     acid; -   (2-{2-[2-(3,5-Dimethyl-isoxazole-4-sulfonylamino)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic     acid; -   (4-Fluoro-2-{2-[2-(3-fluoro-benzenesulfonylamino)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Fluoro-2-{2-[2-(2-fluoro-benzenesulfonylamino)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (2-{2-[2-(3,4-Difluoro-benzenesulfonylamino)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic     acid; -   (2-{2-[2-(N-Benzenesulfonyl-N-methyl-amino)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic     acid; -   [4-Fluoro-2-(2-{2-[N-(3-fluoro-benzenesulfonyl)-N-methyl-amino]-acetyl}-1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic     acid; -   [2-(2-{2-[N-(3,4-Difluoro-benzenesulfonyl)-N-methyl-amino]-acetyl}-1,2,3,4-tetrahydro-isoquinolin-1-yl)-4-fluoro-phenoxy]-acetic     acid; -   1-(5-Carbamoyl-2-carboxymethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-[2-Carboxymethoxy-5-(5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-4-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-6-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-[2-(3-Carboxy-propoxy)-5-fluoro-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   {4-Cyano-2-[2-(trans-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   1-(2-Carboxymethoxy-5-cyano-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   (R)-1-[2-(1-Carboxy-ethoxy)-5-chloro-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   (S)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-fluoro-phenyl)-5-methanesulfonylamino-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-[1,2,3]triazol-1-yl-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-[1,2,3]triazol-2-yl-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; and -   {4-Chloro-2-[2-(2-methoxy-benzylthiocarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid;     or salts (in particular pharmaceutically acceptable salts) of such     compounds;     it is to be understood for any of the above listed compounds, that a     stereogenic center, which is not specifically assigned, may be in     absolute (R)- or absolute (S)-configuration and that a double bond,     which is not specifically assigned, may be in (E)- or     (Z)-configuration; for example, the stereogenic center at the     1-position of the 1,2,3,4-tetrahydroisoquinoline core-structure may     be in absolute (R)-configuration or absolute (S)-configuration (and     preferably in absolute (S)-configuration). Notably, compounds     containing more than one stereogenic center may be at each     stereogenic center, which is not specifically assigned, in absolute     (R)- or absolute (S)-configuration; for example a compound listed as     {4-Fluoro-2-[2-(trans-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid may be     2-{4-fluoro-2-[(S)-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]-phenoxy}-acetic     acid,     2-{4-fluoro-2-[(S)-2-((1S,2S)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]-phenoxy}-acetic     acid,     2-{4-fluoro-2-[(R)-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]-phenoxy}-acetic     acid,     2-{4-fluoro-2-[(R)-2-((1S,2S)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]-phenoxy}-acetic     acid or a mixture thereof (and preferably     2-{4-fluoro-2-[(S)-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]-phenoxy}-acetic     acid or     2-{4-fluoro-2-[(S)-2-((1S,2S)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]-phenoxy}acetic     acid).     58) Further preferred compounds of formula (I) as defined in     embodiment 1) are selected from the group consisting of: -   1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-bromo-benzyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-1,3-dihydro-isoindole-2-carboxylic     acid benzyl ester; -   {4-Chloro-2-[(S)-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-methoxy-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-fluoro-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-methyl-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-trifluoromethyl-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3-methoxy-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3-fluoro-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3-methyl-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3-trifluoromethyl-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2,4-dichloro-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2,3-dichloro-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2,6-dichloro-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2,6-dimethoxy-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2,4-dimethyl-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2,3-dimethyl-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2,6-dimethyl-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2,4-difluoro-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2,3-difluoro-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2,6-difluoro-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2,4,6-trimethyl-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-chloro-6-fluoro-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2,5-dichloro-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2,4-dimethoxy-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2,3-dimethoxy-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2,6-dimethyl-pyridin-3-ylmethyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3-cyano-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2,5-difluoro-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 5-chloro-2-fluoro-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-chloro-5-fluoro-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid cyclohexylmethyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 1-methyl-1H-pyrazol-3-ylmethyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid cyclopentylmethyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid isobutyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid butyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-methoxy-ethyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid cyclopropylmethyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3,5-dimethyl-pyrazol-1-ylmethyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 5-methyl-isoxazol-3-ylmethyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 1,5-dimethyl-1H-pyrazol-3-ylmethyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 4-chloro-benzyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid thiazol-2-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-(4-methyl-thiazol-5-yl)-ethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 5-methyl-thiazol-2-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 4-methyl-thiazol-2-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-methyl-thiazol-5-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-methyl-thiazol-4-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3-methyl-isoxazol-5-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 4-methyl-isoxazol-3-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3,5-dimethyl-isoxazol-4-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid pyrazin-2-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid pyrimidin-4-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid pyrimidin-5-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid phenethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-(3-fluoro-phenyl)-ethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-methyl-2H-pyrazol-3-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2,5-dimethyl-2H-pyrazol-3-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-(2-ethyl-5-methyl-2H-pyrazol-3-yl)-ethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3-methyl-3H-imidazol-4-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-(3,5-dimethyl-pyrazol-1-yl)-ethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 4-methyl-pyrazol-1-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzothiazol-2-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzooxazol-2-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 1-methyl-1H-indazol-3-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid indazol-1-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzo[d]isoxazol-3-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid thiazol-2-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-(4-methyl-thiazol-5-yl)-ethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 5-methyl-thiazol-2-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 4-methyl-thiazol-2-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-methyl-thiazol-5-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-methyl-thiazol-4-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3-methyl-isoxazol-5-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 4-methyl-isoxazol-3-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3,5-dimethyl-isoxazol-4-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid pyrazin-2-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid pyrimidin-4-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid phenethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-(3-fluoro-phenyl)-ethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-methyl-2H-pyrazol-3-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2,5-dimethyl-2H-pyrazol-3-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-(2-ethyl-5-methyl-2H-pyrazol-3-yl)-ethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3-methyl-3H-imidazol-4-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-(3,5-dimethyl-pyrazol-1-yl)-ethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 4-methyl-pyrazol-1-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzothiazol-2-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzooxazol-2-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 1-methyl-1H-indazol-3-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid indazol-1-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzo[d]isoxazol-3-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid thiazol-2-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-(4-methyl-thiazol-5-yl)-ethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 5-methyl-thiazol-2-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 4-methyl-thiazol-2-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-methyl-thiazol-5-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-methyl-thiazol-4-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3-methyl-isoxazol-5-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 4-methyl-isoxazol-3-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid pyrazin-2-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid pyrimidin-4-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid pyrimidin-5-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid phenethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-(3-fluoro-phenyl)-ethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-methyl-2H-pyrazol-3-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2,5-dimethyl-2H-pyrazol-3-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-(2-ethyl-5-methyl-2H-pyrazol-3-yl)-ethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3-methyl-3H-imidazol-4-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-(3,5-dimethyl-pyrazol-1-yl)-ethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 4-methyl-pyrazol-1-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzothiazol-2-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzooxazol-2-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 1-methyl-1H-indazol-3-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid indazol-1-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzo[d]isoxazol-3-ylmethyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-fluoro-benzyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3-fluoro-benzyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2,3-difluoro-benzyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-fluoro-benzyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3-fluoro-benzyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2,3-difluoro-benzyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3-fluoro-benzyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-methoxy-benzyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-fluoro-benzyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3-fluoro-benzyl ester; -   (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 2-fluoro-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 4-methyl-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 4-methoxy-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 4-fluoro-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 4-trifluoromethyl-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid 3-chloro-benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-7-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   (4-Chloro-2-{2-[3-(5-fluoro-3-methyl-indol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(6-methoxy-pyrrolo[2,3-b]pyridin-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(4,6-dimethoxy-pyrrolo[2,3-b]pyridin-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(4,6-dimethoxy-indol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   {4-Chloro-2-[2-(3-indol-1-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   (4-Chloro-2-{2-[3-(5-fluoro-indol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(7-chloro-indol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   {4-Chloro-2-[2-(3-pyrrolo[3,2-b]pyridin-1-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   (4-Chloro-2-{2-[3-(4-methoxy-indol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(3-chloro-indazol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(6-methyl-indol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(6-chloro-indol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(4-fluoro-indol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(6-fluoro-indol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(6-methoxy-indol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{(S)-6-fluoro-2-[3-(5-fluoro-indazol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{(S)-6-fluoro-2-[3-(3-methyl-indazol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{(S)-2-[3-(6-chloro-indazol-1-yl)-propionyl]-6-fluoro-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(3-chloro-pyrrolo[2,3-b]pyrazin-5-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[2-(2-methoxy-phenoxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[2-(4-fluoro-phenoxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[2-(quinolin-8-yloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[2-(4-chloro-phenoxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[trans-2-(4-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[trans-2-(3-chloro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   {4-Chloro-2-[2-(trans-2-o-tolyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   (4-Chloro-2-{2-[trans-2-(2-trifluoromethyl-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[trans-2-(3-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[trans-2-(3-methoxy-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   {4-Chloro-2-[2-(trans-2-m-tolyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   {4-Chloro-2-[6-fluoro-2-(trans-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   (4-Chloro-2-{6-fluoro-2-[trans-2-(2-trifluoromethyl-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[2-(trans-2-chloro-phenyl)-cyclopropanecarbonyl]-6-fluoro-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   {4-Chloro-2-[6-fluoro-2-(trans-2-o-tolyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   (4-Chloro-2-{2-[2-(2,6-dimethyl-pyridin-3-yloxy)-acetyl]-6-fluoro-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{6-fluoro-2-[3-(1-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   {4-Chloro-2-[6-fluoro-2-(3-o-tolyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   (4-Chloro-2-{6-fluoro-2-[4-(2-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[2-(2-chloro-benzyloxy)-acetyl]-6-fluoro-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   {4-Chloro-2-[2-(3-2,3-dihydro-indol-1-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   (4-Chloro-2-{2-[3-(3-methyl-indol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   {4-Chloro-2-[2-(3-indazol-1-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   {4-Chloro-2-[2-(3-3,4-dihydro-2H-quinolin-1-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   (4-Chloro-2-{2-[2-(2,4-dimethyl-phenoxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(5-methoxy-1-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   {4-Chloro-2-[2-(3-1H-indol-3-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   {4-Chloro-2-[2-(2,2-dimethyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   {4-Chloro-2-[2-(2-chloro-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   {4-Chloro-2-[2-(3-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   [2-(2-Benzylcarbamoyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-4-chloro-phenoxy]-acetic     acid; -   [4-Chloro-2-(2-phenethylcarbamoyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic     acid; -   {4-Chloro-2-[2-(4-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   {4-Chloro-2-[2-(2-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   1-(2-Carboxymethoxy-5-fluoro-phenyl)-1,3-dihydro-isoindole-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-5-fluoro-1,3-dihydro-isoindole-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-4-fluoro-1,3-dihydro-isoindole-2-carboxylic     acid benzyl ester; -   {4-Chloro-2-[2-trans-(2-phenyl-cyclopropanecarbonyl)-2,3-dihydro-1H-isoindol-1-yl]-phenoxy}-acetic     acid; -   (4-Chloro-2-{2-[2-(4-fluoro-phenoxy)-acetyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[2-(quinolin-8-yloxy)-acetyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(5-methoxy-1H-indol-3-yl)-propionyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[2-(2,6-dimethyl-pyridin-3-yloxy)-acetyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(1-methyl-1H-indol-3-yl)-propionyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic     acid; -   {4-Chloro-2-[2-(3-2,3-dihydro-indol-1-yl-propionyl)-2,3-dihydro-1H-isoindol-1-yl]-phenoxy}-acetic     acid; -   {4-Chloro-2-[2-(3-indazol-1-yl-propionyl)-2,3-dihydro-1H-isoindol-1-yl]-phenoxy}-acetic     acid; -   (4-Chloro-2-{2-[2-(5-methoxy-benzo[d]isoxazol-3-yl)-acetyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(3-methyl-indol-1-yl)-propionyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[2-(2-chloro-benzyloxy)-acetyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(2-fluoro-phenoxy)-propionyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-trans-[2-(3-fluoro-phenyl)-cyclopropanecarbonyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-trans-[2-(2-fluoro-phenyl)-cyclopropanecarbonyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic     acid; -   {4-Chloro-2-[5-fluoro-2-(3-indazol-1-yl-propionyl)-2,3-dihydro-1H-isoindol-1-yl]-phenoxy}-acetic     acid; -   (4-Chloro-2-{2-[3-(5-fluoro-indazol-1-yl)-propionyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(4-fluoro-3-methyl-indazol-1-yl)-propionyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(6-fluoro-3-methyl-indazol-1-yl)-propionyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(6-chloro-3-methyl-indazol-1-yl)-propionyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(3-methyl-indazol-1-yl)-propionyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(6-fluoro-indazol-1-yl)-propionyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(4-fluoro-indazol-1-yl)-propionyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{2-[3-(7-fluoro-indazol-1-yl)-propionyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic     acid; -   {4-Chloro-2-[2-(2-fluoro-benzylcarbamoyl)-2,3-dihydro-1H-isoindol-1-yl]-phenoxy}-acetic     acid; -   {4-Chloro-2-[2-(3-fluoro-benzylcarbamoyl)-2,3-dihydro-1H-isoindol-1-yl]-phenoxy}-acetic     acid; -   {4-Chloro-2-[2-(4-fluoro-benzylcarbamoyl)-2,3-dihydro-1H-isoindol-1-yl]-phenoxy}-acetic     acid; -   [2-(2-Benzylcarbamoyl-2,3-dihydro-1H-isoindol-1-yl)-4-chloro-phenoxy]-acetic     acid; -   [4-Chloro-2-(2-phenethylcarbamoyl-2,3-dihydro-1H-isoindol-1-yl)-phenoxy]-acetic     acid; -   {4-Chloro-2-[2-(2-chloro-benzylcarbamoyl)-2,3-dihydro-1H-isoindol-1-yl]-phenoxy}-acetic     acid; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-4,5-dichloro-1,3-dihydro-isoindole-2-carboxylic     acid benzyl ester; -   1-(2-Carboxymethoxy-5-chloro-phenyl)-4,5-difluoro-1,3-dihydro-isoindole-2-carboxylic     acid benzyl ester; -   {4-Chloro-2-[(S)-2-((1R,2R)-2-o-tolyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic     acid; -   (4-Chloro-2-{(S)-2-[(1R,2R)-2-(2-trifluoromethyl-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{(S)-2-[(1R,2R)-2-(3-chloro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{(S)-2-[(1R,2R)-2-(3-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (4-Chloro-2-{(S)-2-[(1R,2R)-2-(4-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic     acid; -   (S)-1-[5-Chloro-2-(2-oxo-2-trifluoromethanesulfonylamino-ethoxy)-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; -   (S)-1-[5-Chloro-2-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-ylmethoxy)-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester; and -   1-[5-Chloro-2-(3-hydroxy-isoxazol-5-ylmethoxy)-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic     acid benzyl ester;     or salts (in particular pharmaceutically acceptable salts) of such     compounds; it is to be understood for any of the above listed     compounds, that a stereogenic center, which is not specifically     assigned, may be in absolute (R)- or absolute (S)-configuration and     that a double bond, which is not specifically assigned, may be in     (E)- or (Z)-configuration; for example, the stereogenic center at     the 1-position of the 1,2,3,4-tetrahydroisoquinoline or isoindoline     core-structure may be in absolute (R)-configuration or absolute     (S)-configuration (and preferably in absolute (S)-configuration).     Notably, compounds containing more than one stereogenic center may     be at each stereogenic center, which is not specifically assigned,     in absolute (R)- or absolute (S)-configuration; for example a     compound listed as     (4-Chloro-2-{2-trans-[2-(2-fluoro-phenyl)-cyclopropanecarbonyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic     acid may be     (4-Chloro-2-{(S)-2-[(1S,2S)-2-(2-fluoro-phenyl)-cyclopropanecarbonyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic     acid,     (4-Chloro-2-{(S)-2-[(1R,2R)-2-(2-fluoro-phenyl)-cyclopropanecarbonyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic     acid,     (4-Chloro-2-{(R)-2-[(1S,2S)-2-(2-fluoro-phenyl)-cyclopropanecarbonyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic     acid,     (4-Chloro-2-{(R)-2-[(1R,2R)-2-(2-fluoro-phenyl)-cyclopropanecarbonyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic     acid or a mixture thereof (and preferably     (4-Chloro-2-{(S)-2-[(1S,2S)-2-(2-fluoro-phenyl)-cyclopropanecarbonyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic     acid or     (4-Chloro-2-{(S)-2-[(1R,2R)-2-(2-fluoro-phenyl)-cyclopropanecarbonyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic     acid).

Unless explicitly stated otherwise, the general terms and names used hereinbefore and hereinafter preferably have within the context of this disclosure the following meanings:

Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases and the like, this is intended to mean also a single compound, salt, pharmaceutical composition, disease or the like.

The term “pharmaceutically acceptable salts” refers to non-toxic, inorganic or organic acid and/or base addition salts. Reference can be made to “Salt selection for basic drugs”, Int. J. Pharm. (1986), 33, 201-217.

The compounds of formula (I) according to any one of embodiments 1) to 58), or pharmaceutically acceptable salts thereof, may be used for the preparation of a medicament, and are suitable for the prevention and/or treatment of diseases selected from the group consisting of chronic and acute allergic/immune diseases/disorders, comprising asthma, allergic asthma, eosinophilic asthma, severe asthma, rhinitis, allergic rhinitis, angioedema, insect venom allergy, drug allergies, allergic sinusitis, allergic nephritis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, ulcerative colitis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease and rheumatoid arthritis; eosinophil-related diseases comprising small vessel vasculitides like Churg-Strauss syndrome, Wegener's granulomatosis, microscopic polyangiitis (and organ-specific subsets of the latter), hypereosinophilic syndromes like eosinophilic pneumonia, eosinophilic esophagitis, reflux esophagitis, eosinohilic endocarditis (Loeffler's endocarditis), eosinophilia-myalgia syndrome, eosinophilic fasciitis, eosinohilic pustular folliculitis (Ofuji's disease), eosinophilic ulcers, angiolymphoid hyperplasia with eosinophilia (ALHE), eosinophilic cellulitis (Wells syndrome), chronic eosinophilic leukemia and DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms); and basophil-related diseases, comprising basophilic leukemia and basophilic leukocytosis.

In a preferred embodiment, the compounds of formula (I) according to any one of embodiments 1) to 58), or pharmaceutically acceptable salts thereof, may be used for the preparation of a medicament, and are suitable for the prevention and/or treatment of diseases selected from the group consisting of asthma, allergic asthma, eosinophilic asthma, severe asthma, allergic rhinitis, angioedema, insect venom allergy, drug allergies, allergic sinusitis, allergic nephritis, allergic conjunctivitis, atopic dermatitis, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria and eczema.

In another preferred embodiment, the compounds of formula (I) according to any one of embodiments 1) to 58), or pharmaceutically acceptable salts thereof, may be used for the preparation of a medicament, and are suitable for the prevention and/or treatment of diseases selected from the group consisting of eosinophil-related diseases comprising small vessel vasculitides like Churg-Strauss syndrome, Wegener's granulomatosis, microscopic polyangiitis (and organ-specific subsets of the latter), hypereosinophilic syndromes like eosinophilic pneumonia, eosinophilic esophagitis, reflux esophagitis, eosinohilic endocarditis (Loeffler's endocarditis), eosinophilia-myalgia syndrome, eosinophilic fasciitis, eosinohilic pustular folliculitis (Ofuji's disease), eosinophilic ulcers, angiolymphoid hyperplasia with eosinophilia (ALHE), eosinophilic cellulitis (Wells syndrome), chronic eosinophilic leukemia and DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms).

In yet another preferred embodiment, the compounds of formula (I) according to any one of embodiments 1) to 58), or pharmaceutically acceptable salts thereof, may be used for the preparation of a medicament, and are suitable for the prevention and/or treatment of diseases selected from the group consisting of basophil-related diseases, comprising basophilic leukemia and basophilic leukocytosis.

The invention also relates to the use of a compound of formula (I) according to any one of embodiments 1) to 58) for the preparation of pharmaceutical compositions for the treatment and/or prophylaxis of the above-mentioned diseases.

The present invention also relates to pharmaceutically acceptable salts and to pharmaceutical compositions and formulations of compounds of formula (I) according to any one of embodiments 1) to 58).

A pharmaceutical composition according to the present invention contains at least one compound of formula (I) according to any one of embodiments 1) to 58) (or a pharmaceutically acceptable salt thereof) as the active agent and optionally carriers and/or diluents and/or adjuvants.

The compounds of formula (I) according to any one of embodiments 1) to 58) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such as especially oral) or parenteral (including topical application or inhalation) administration.

The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, “Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds of formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.

The present invention also relates to a method for the prevention or treatment of a disease or disorder mentioned herein comprising administering to a subject a pharmaceutically active amount of a compound of formula (I) according to any one of embodiments 1) to 58), or a pharmaceutically acceptable salt thereof.

The present invention also includes isotopically labelled, especially ²H (deuterium) labelled compounds of formula (I), which compounds are identical to the compounds of formula (I) except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Isotopically labelled, especially ²H (deuterium) labelled compounds of formula (I) and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope ²H (deuterium) may lead to greater metabolic stability, resulting e.g. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile. In one embodiment of the invention, the compounds of formula (I) are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of formula (I) are not isotopically labelled at all. Isotopically labelled compounds of formula (I) may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.

Any reference to a compound of formula (I), (I_(ST1)), (I_(ST2)), (I_(P)), (I-1), (I-2), (I-3), (I_(ISO)) or (I_(TET)), in this text is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient. The preferences indicated for the compounds of formula (I) of course apply mutatis mutandis to the compounds of formula (I_(ST1)), the compounds of formula (I_(ST2)), the compounds of formula (I_(P)), the compounds of formula (I-1), the compounds of formula (I-2), the compounds of formula (I-3), the compounds of formula (I_(ISO)) and the compounds of formula (I_(TET)) as well as to the salts and pharmaceutically acceptable salts of the compounds of formula (I), of formula (I_(ST1)), of formula (I_(ST2)), of formula (I_(P)), of formula (I-1), of formula (I-2), of formula (I-3), of formula (I_(ISO)) or of formula (I_(TET)). The same applies to these compounds as medicaments, to pharmaceutical compositions containing these compounds as active principles or to the uses of these compounds for the manufacture of a medicament for the treatment of the diseases according to this invention.

Unless used regarding temperatures, the term “about” (or alternatively “around”) placed before a numerical value “X” refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X. In the particular case of temperatures, the term “about” (or alternatively “around”) placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 10° C. to Y plus 10° C., and preferably to an interval extending from Y minus 5° C. to Y plus 5° C. Besides, the term “room temperature” (r.t.) as used herein refers to a temperature of about 25° C.

Whenever the word “between” is used to describe a numerical range, it is to be understood that the end points of the indicated range are explicitly included in the range. For example: if a temperature range is described to be between 40° C. and 80° C., this means that the end points 40° C. and 80° C. are included in the range or if a variable is defined as being an integer between 1 and 4, this means that the variable is the integer 1, 2, 3, or 4.

As mentioned earlier, compounds of formula (I) modulate the PGD₂ activation of the CRTH2 receptor. The biological effect of such compounds may be tested in a variety of in vitro, ex vivo and in vivo assays. The ability of the compounds of formula (I) to bind to the CRTH2 receptor may be measured by methods similar to those described in the literature (Arimura A. et al., J. Pharmacol. Exp. Ther. 2001, 298(2), 411-419; and Sawyer N. et al., Br. J. Pharmacol, 2002, 137, 1163-1172, respectively) and by the assays described below in the experimental part.

A further aspect of the invention is a process for the preparation of compounds of Formula (I). Compounds according to Formula (I) of the present invention can be prepared according to the sequence of reactions outlined in the schemes below wherein X, Y, Z, n, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are as defined for Formula (I). Other abbreviations used are defined in the experimental section. In some instances the generic groups X, Y, Z, n, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ might be incompatible with the assembly illustrated in the schemes below and, therefore, will require the use of protecting groups (PG). For example it may be necessary to protect reactive functional groups such as hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. The use of protecting groups is well known in the art (see for example “Protective Groups in Organic Synthesis”, T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999). It will be assumed that such protecting groups are as necessary in place. In the following description, for example, “PG”, when used as amino-protecting group, preferably refers to a group such as tert-butoxycarbonyl, benzyloxycarbonyl, or allyloxycarbonyl, most preferably benzyloxycarbonyl. Further, “L” refers to a leaving group, such as an activated hydroxy group (for examples as mesylate, tosylate, active ester etc.), an in-situ activated hydroxy group (as used, for instance, in Mitsunobu reactions), or a halogen, in particular chloro or bromo. Further, “R” refers to a (C₁-C₄)alkyl group, preferably methyl, ethyl or tert-butyl.

In general, all chemical transformations can be performed according to well-known standard methodologies as described in the literature or as described in the procedures below. The compounds obtained may also be converted into pharmaceutically acceptable salts thereof in a manner known per se.

Generally, compounds of Formula (I), wherein R¹⁰ represents —COOH, are obtained from an ester of Structure 1, wherein R represents (C₁-C₄)alkyl (preferably methyl, ethyl, or tert-butyl) by hydrolysis of the ester group using routine procedures, for example by stirring an intermediate of Structure 1, wherein R represents methyl or ethyl, with an aqueous solution of LiOH, NaOH or KOH in an organic co-solvent such as an alcohol (like MeOH or EtOH), THF, acetone, MeCN, or DMF; or by stirring an intermediate of Structure 1, wherein R represents tert.-butyl, in an acid like TFA.

An intermediate of Structure 1 is for instance obtained by reacting an intermediate of Structure 2, or a salt thereof, such as a hydrochloride salt, with a reagent of Formula L-C(O)X—R¹, wherein X and R¹ are as defined for Formula (I) and L is a leaving group such as an halogen (in particular chloro), in the presence of a base like NEt₃, DIPEA, N-ethyl-morpholine, N-methylpiperidine, or pyridine, in a suitable solvent, such as THF, or DCM. The starting material L-C(O)X—R¹ may be a chloroformate; an acyl anhydride; or an acyl halide like an acid chloride or an acid bromide. The acyl halide may be commercially available, known in the art or obtainable in situ from the corresponding commercially available or well known carboxylic acid in a reaction with a halogenating reagent like oxalyl chloride or phosphorous oxychloride under conditions known to a skilled person.

In another aspect, an intermediate of Structure 2 is reacted with a commercially available or well known isocyanate or isothiocyanate in the presence of a base to form an intermediate of Structure 1.

In another aspect, an intermediate of Structure 2 is activated with triphosgene, CDI, or the like and the reactive intermediate is then treated with an alcohol or an amine to give an intermediate of Structure 1, wherein X represents —NH— or —O—.

In a further aspect, an intermediate of Structure 2 is condensed with a commercially available or well known carboxylic acid in the presence of a coupling reagent, such as EDC, TBTU, diisopropylcarbodiimide, HATU, DCC, Ghosez's reagent or the like, in the presence of a base like NEt₃, DIPEA, or pyridine to form an intermediate of Structure 1.

In a further aspect, an intermediate of Structure 2 is reacted with bromoacetyl bromide in the presence of a base like NEt₃ or DIPEA to give the bromide 3, which is then used in an etherification reaction with alcohols R^(A)OH (wherein R^(A) represents optionally substituted aryl-(C₁-C₂)alkyl or optionally substituted heteroaryl-(C₁-C₂)alkyl) in the presence of a base like sodium hydride to give a compound of Structure 1-A (Scheme 1). Alternatively, an intermediate of Structure 2 is used in an amide coupling with a N-protected amino acid to give an amide 4. Deprotection (for example catalytic hydrogenolysis of a Cbz protecting group), followed by reaction of the resulting amine with a sulfonyl chloride R^(B)SO₂Cl (wherein R^(B) represents optionally substituted aryl or optionally substituted heteroaryl) yields a derivative of Structure 1-B. The resulting sulfonamide may be alkylated with Me-L (wherein L is a bromide or iodide) in the presence of a base like sodium hydride to give an intermediate of Structure 1-C (Scheme 2).

In another aspect an intermediate of Structure 2 is reacted with a carbonate 5 (wherein R^(C) represents optionally substituted aryl) in the presence of a base like NEt₃ or DIPEA to give an intermediate of Structure 1-D (Scheme 3). A carbonate 5 is prepared by reaction of a benzyl alcohol 6 with N,N′-disuccinimidyl carbonate in the presence of a base like DMAP.

Alternatively an intermediate of Structure 2 is condensed with 4-nitrophenyl chloroformate in the presence of a base like NEt₃ or DIPEA to give a carbamate 7 (Scheme 4). The carbamate 7 is then treated with an alcohol R^(E)OH (wherein R^(E) represents (C₁-C₄)alkyl which is mono-substituted with (C₃-C₆)cycloalkyl, (C₁-C₄)alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted aryl-(C₁-C₂)alkoxy, optionally substituted heteroaryl-(C₁-C₂)alkoxy, optionally substituted heteroarylsulfanyl or —NR⁸R⁹) in the presence of potassium tert-butoxide to give a compound of Formula (I-A). Under these specific conditions, the saponification and the substitution take place during the same reaction.

In another alternative, an intermediate of Structure 2 is treated with acryloyl chloride in the presence of a base like NEt₃ or DIPEA to give the vinyl amide 8 (Scheme 5). The vinyl amide 8 can undergo a Michael addition with R^(G)H (9), wherein R^(G)H represents an optionally substituted heteroaryl group containing an hydrogenated nitrogen atom in the ring system, like an optionally substituted indole, azaindole or indazole derivative. The reaction may be performed in the presence of potassium fluoride on alumina (F. M. Moghaddam et al., Lett. Org. Chem. 2006, 3, 157-160) and takes place at the nitrogen atom of the heteroaryl group to give a compound of Formula (I-B). Under these specific reaction conditions, potassium hydroxide is generated and the Michael addition and the saponification take place during the same reaction.

An intermediate of Structure 2 is obtained after removal of a protecting group (PG) from an intermediate of Structure 10, applying reaction conditions known to a skilled person. Preferably, PG is a group such as tert-butoxycarbonyl or benzyloxycarbonyl. A benzyloxycarbonyl protecting group is removed by hydrogenolysis or treatment with an acid; a tert-butoxycarbonyl group is cleaved under acidic conditions.

An intermediate of Structure 10, wherein n represents 1 (a tetrahydroisoquinoline) is obtained by one of the synthetic pathways described below. For example, an intermolecular α-aminoalkylation reaction between a 3,4-dihydroisoquinoline 11 and a phenol 12 (Scheme 6) gives the tetrahydroisoquinoline 13. In this reaction, the 3,4-dihydroisoquinoline 11 is first activated at r.t. in MeCN with a protecting group precursor PGL such as di-tert-butyl dicarbonate or a chloroformate (like benzyl chloroformate). The resulting activated species undergoes an electrophilic substitution with an electron rich aromatic compound (such as phenol 12) in MeCN at a temperature of about 60-80° C. A subsequent alkylation of phenol 13 with an electrophile L-Y—CO₂R, wherein Y is as defined in Formula (I) and L is a leaving group such as bromide, in the presence of a base like Cs₂CO₃ or K₂CO₃ affords an intermediate of Structure 10 (n=1).

In another aspect, treatment of a dihydroisoquinoline 11 with a protecting group precursor PG¹L such as di-tert-butyl dicarbonate or a chloroformate (like benzyl chloroformate), followed by the addition of a Grignard reagent 14 affords the tetrahydroisoquinoline 15 (Scheme 3). The Grignard reagent 14 is prepared by treatment of the bromide 16 with a solution of isopropylmagnesium chloride/lithium chloride complex. Compound 16 is obtained through protection of the phenol 17 with an allyl halide (e.g. allyl bromide) or a benzyl halide (e.g. benzyl bromide) as protecting group precursor PG²L in the presence of a base like K₂CO₃ in a solvent like acetone. Selective deprotection of the phenol protecting group of structure 15, like an selective removal of an allyl group in the presence of a carbamate protecting group (PG¹) with Pd(PPh₃)₄ and a barbituric acid derivative and a subsequent alkylation with an electrophile L-Y—CO₂R, wherein Y is as defined in Formula (I) and L is a leaving group such as bromide, in the presence of a base like Cs₂CO₃ or K₂CO₃ yields an intermediate of Structure 10-A.

In another aspect, Suzuki reaction of bromide 18 with a boronic acid R⁵B(OH)₂ in the presence of a palladium catalyst affords an intermediate of Structure 10-B. A bromide 18 could also be used in a Stifle cross-coupling reaction. A bromide 18 can also be converted into a sulfone of Structure 10-C using a sulfinate derivative R^(I)S(O)ONa (wherein R^(I) represents (C₁-C₄)alkyl or phenyl) in the presence of a copper catalyst like CuI and a ligand like prolinate. Finally, a bromide 18 can be converted into a triazole derivative of Structure 10-D using a copper catalyst like CuI in the presence of a bidentate ligand like N,N′-dimethyl-1,2-cyclohexanediamine (Scheme 8).

Alternatively, a bromide 19 can be converted in a sulfone of Structure 10-E using a sulfinate derivative R^(I)S(O)ONa (wherein R^(I) represents (C₁-C₄)alkyl or phenyl) in the presence of a copper catalyst like CuI and a ligand like prolinate. A bromide 19 can be converted into a sulphonamide of Structure 10-F using a sulphonamide derivative R^(J)SO₂NH₂ (wherein R^(J) represents (C₁-C₄)alkyl) in the presence of a copper catalyst like CuI in the presence of a bidentate ligand like N,N-dimethylglycine (Scheme 9).

In another aspect, a nitrile 20, obtainable following the sequence depicted in Scheme 6 (R⁵═CN), is converted to an amide of Structure 10-G by nitrile hydrolysis using water and the platinum catalyst developed by Ghaffar et al. (Tet. Lett. 1995, 36, 8657). Alternatively, nitrile 20 is transformed into an oxadiazole derivative by condensation with hydroxylamine and thiocarbonyldiimidazole (Scheme 10).

The required 3,4-dihydroisoquinolines 11 are prepared from the corresponding phenethylamines 21 (or the corresponding hydrochloride salts) using a modified Bischler-Napieralski reaction (Scheme 11). Thus, reaction of a phenethylamine 21 with ethyl formate affords the corresponding formamide, which is transformed into an oxazolo intermediate upon treatment with oxalyl chloride and iron(III) chloride. Treatment of the oxazolo derivative with methanol in the presence of an acid like sulphuric acid yields the desired 3,4-dihydroisoquinolines 11. If not commercially available, the phenethylamines 21 may be synthesized by reduction of the corresponding α,β-unsaturated nitro derivatives 22, which are prepared from the aldehydes 23 through an Henry reaction. Alternatively, the phenethylamines 21, wherein R⁷ represents methyl, are obtained from the corresponding benzyl cyanide 24 through double alkylation with methyl iodide in the presence of a base like sodium hydroxide followed by a reduction of the nitrile with lithium aluminum hydride. Finally, dihydroisoquinolines 11 can be obtained by oxidation of the corresponding tetrahydroisoquinolines 25 with N-bromosuccinimide followed by a basic workup (Scheme 11).

An intermediate of Structure 10, wherein n represents 0 (an isoindoline) may be prepared as described in Scheme 12. The bromide 26 is submitted to a lithium halogen exchange mediated by nBuLi and the resulting lithiated species is treated with the sulfinamide 27 to afford the isoindoline 28. The sulfinamide auxiliary is then cleaved under acidic conditions (for example in the presence of HCl) and the resulting amine is treated with a protecting group precursor PG¹L such as di-tert-butyl dicarbonate or a chloroformate (like benzyl chloroformate) to give the isoindoline 29. Selective deprotection of the phenol protecting group of structure 29, like an selective removal of an allyl group in the presence of a carbamate protecting group (PG¹) with Pd(PPh₃)₄ and a barbituric acid derivative gives a phenol 30. Alkylation of compound 30 with an electrophile L-Y—CO₂R, wherein Y is as defined in Formula (I) and L is a leaving group such as bromide, in the presence of a base like Cs₂CO₃ or K₂CO₃ yields an intermediate of Structure 10-J. Compound 27 is prepared from salicylaldehyde derivative 31 through protection of the phenol moiety with an allyl halide (e.g. PG²L=allyl chloride) or a benzyl halide (e.g. PG²L=benzyl bromide) in the presence of a base like potassium carbonate in a solvent like DMF. The aldehyde 32 is treated with tert-butylsulfinamide in the presence of Ti(OEt)₄ in a solvent like THF to give the sulfinamide 27.

The required bromides 26 are prepared from the corresponding benzyl alcohols 33 through a chlorination with thionyl chloride (Scheme 13). If not commercially available, the benzyl alcohols 33 are synthesized by reduction of the corresponding aldehydes 34 by using, for instance, sodium borohydride in a solvent like MeOH. The aldehydes 34 can be prepared from the corresponding bromide 35 through deprotonation with a strong base like LDA and subsequent addition of DMF.

In another aspect, the carboxylic acid moiety in compounds of Formula (I—C) can be replaced by a bioisostere. For example, the carboxylic acid can undergo an amide coupling with hydrazine in the presence of a coupling reagent like TBTU and a base such as DIPEA to give an hydrazide intermediate 36. The hydrazide 36 can then undergo a CDI mediated cyclization in the presence of a base like NEt₃ to form a 5-oxo-4,5-dihydro-[1,3,4]oxadiazol derivative of Formula (I-D) (Scheme 14). Alternatively, an amide coupling between the carboxylic acid moiety and trifluoromethanesulfonamide in the presence of a coupling reagent like HATU and a base such as DIPEA gives a trifluoromethylsulfonamido derivative of Formula (I-E). In another aspect, the carboxylic acid moiety can undergo an amide coupling with cyanamide in the presence of a coupling reagent such as HATU and a base like NEt₃ to give a cyanamido derivative of Formula (I-F) (Scheme 14).

Alternatively, an ester of Structure 1 can be treated with aqueous hydroxylamine in a solvent like isopropanol to form an hydroxamate of Formula (I-G) (Scheme 15).

In another aspect, the known alcohol 37 (R. Riess et al., Eur. J. Org. Chem. 1998, 473-479) can be converted into the mesylate 38 by treatment with mesylchloride in the presence of a base like NEt₃. The mesylate 38 is then used to alkylate a phenol derivative 13 (n=1) or 30 (n=0) in the presence of a base like potassium carbonate (Scheme 16). Global deprotection mediated by for example hydrobromic acid in acetic acid leads to the intermediate 39, which can be transformed in a compound of Formula (I-H) following one of the synthetic pathways describing the transformation of a compound of Structure 2 into a compound of Formula I (see above).

Alternatively, a phenol 13 (n=1) or 30 (n=0) can be alkylated with chloroacetonitrile in the presence of a base such as potassium carbonate to give a nitrile derivative 40 (Scheme 17). Protecting group removal under acidic conditions and introduction of the desired residue R¹—X—C(Z)— as described for the transformation of a compound of Structure 2 into a compound of Formula (I) gives an intermediate 41. The nitrile derivative 41 can be converted into a tetrazole of Formula (I-J) by treatment with sodium azide. In a different approach, a compound 41 can react with hydroxylamine in the presence of a base like potassium carbonate. The resulting N-hydroxycarbamimidoyl derivative 42 may undergo a CDI mediated cyclization in the presence of a base such as DBU to give a 5-oxo-4,5-dihydro-[1,2,4]oxadiazol derivative of Formula (I-K).

Acid derivatives used in the amide coupling with compounds of Structure 2 are commercially available, known in the art or obtainable according to Schemes 18 and 19. A Negishi cross-coupling reaction between the bromo derivative 43, wherein R^(K) and R^(L) independently represent hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, chloro, or fluoro, and a zinc bromide derivative affords the ester 44 which is saponified to the corresponding carboxylic acid 45 (Scheme 18).

Alternatively, a cinnamic acid 46, wherein R^(M) and R^(N) independently represent hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)fluoroalkyl, or halogen, is converted to the Weinreb amide 47. Corey-Chaykovsky cyclopropanation gives the cyclopropane 48, which is hydrolyzed to the corresponding carboxylic acid 49 (Scheme 19).

Whenever the compounds of Formula (I) are obtained in the form of mixtures of enantiomers or diastereoisomers, the enantiomers or diastereoisomers can be separated using methods known to one skilled in the art: e.g. by formation and separation of diastereomeric salts or by HPLC over a chiral stationary phase such as a Daicel ChiralPak AD-H (5 μm) column, a Daicel ChiralCel OD-H (5 μm) column, a Daicel ChiralCel OD (10 μm) column, a Daicel ChiralPak IA (5 μm) column, a Daicel ChiralPak IB (5 μm) column, a Daicel ChiralPak IC (5 μm) column, or a (R,R)-Whelk-01 (5 μm). Typical conditions of chiral HPLC are an isocratic mixture of eluent A (EtOH, in presence or absence of a base like NEt₃ and/or diethylamine or of an acid like TFA) and eluent B (heptane), at a flow rate of 8 to 34 mL/min.

Experimental Section: Abbreviations (as Used Herein):

AcOEt Ethyl acetate AcOH Acetic acid aq. aqueous

Bdg Binding BSA Bovine Serum Albumin

Bu n-butyl ca. circa (latin)—approximately

Cbz Benzyloxycarbonyl

CC Column chromatography on silica gel

CDI Carbonyldiimidazole

comb. combined conc. concentrated DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene

DCC 1,3-Dicyclohexylcarbodiimide DCM Dichloromethane DIPEA N,N-Diisopropylethylamine

DMAP N,N-Dimethyl-4-aminopyridine

DME 1,2-Dimethoxyethane DMF Dimethylformamide DMSO Dimethylsulfoxide

dpm decays per minute

EDTA Ethylene Diamine Tetraacetic Acid

EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide ee enantiomeric excess eq. Equivalent EtOH ethanol

ESI-MS Electrospray Ionization Mass Spectroscopy

Ghosez's reagent 1-Chloro-N,N,2-trimethyl-1-propenylamine h hour(s) HATU O-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

Hept Heptane HPLC High Performance Liquid Chromatography

HSA human serum albumin hv high vacuum iPr isopropyl L liter(s) LAH lithium aluminum hydride

LC-MS Liquid Chromatography—Mass Spectroscopy

M molarity [mol L⁻¹]

Me Methyl MeCN Acetonitrile

MeI Methyl iodide

MeOH Methanol

mesyl Methanesulfonyl Meth. Method min minute(s)

MS Mass Spectroscopy MW Molecular Weight

N Normality of solution

NBS N-bromo-succinimide NEt₃ Triethylamine

NMR Nuclear magnetic resonance org. organic

PBS Phosphate Buffered Saline PG Protecting Group PGD₂ Prostaglandin D₂

PMSF Phenylmethylsulfonyl fluoride prep. preparative r.t. room temperature second(s) sat. saturated Si-carbonate Polymer supported carbonate Si-DEA Polymer supported diethyl amine soln. solution subst. Substituted TBTU O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tert. tertiary TFA Trifluoroacetic acid

THF Tetrahydrofuran

tosyl Toluenesulfonyl t_(R) retention time Tris Tris-(hydroxymethyl)aminomethane buffer

Chemistry General Remarks

All solvents and reagents are used as obtained from commercial sources unless otherwise indicated.

Temperatures are indicated in degrees Celsius (° C.). Unless otherwise indicated, the reactions take place at room temperature (r.t.).

In mixtures, relations of parts of solvent or eluent or reagent mixtures in liquid form are given as volume relations (v/v), unless indicated otherwise.

Analytical HPLC conditions as used in the Examples below:

LC-MS 1

LC-MS-conditions: Analytical. Pump: Waters Acquity Binary Solvent Manager, MS: Waters SQ Detector, DAD: Acquity UPLC PDA Detector, ELSD: Acquity UPLC ELSD. Column: Acquity UPLC BEH C18 1.7 mm 2.1×50 mm ID from Waters, thermostated in the Acquity UPLC Column Manager. Eluents: A: H₂O+0.05% formic acid or TFA; B: MeCN+0.05% formic acid or TFA. Method: Gradient: 2% B to 98% B over 2.00 min. Flow: 1.2 mL/min. Detection: UV/Vis and/or ELSD, and MS, t_(R) is given in min

LC-MS 1 FA: Eluents: A: H₂O+0.05% formic acid; B: MeCN+0.05% formic acid

LC-MS 1TFA: Eluents: A: H₂O+0.05% TFA; B: MeCN+0.05% TFA

LC-MS 2 to LC-MS 5

HPLC/MS analyses are performed on a Ultimate 3000RS Dionex HPLC instrument, equipped with a Dionex Ultimate 3000 RS Photodiode Array Detector, a Dionex Ultimate 3000RS pump and a Dionex MSQ⁺ mass spectrometer.

The LC retention times are obtained using the following elution conditions:

-   -   LC-MS 2: Analytical HPLC on a Waters X-Bridge C18 column (4.6×30         mm, 2.5 μm, Waters); Linear gradient of water/0.04% TFA (A) and         MeCN (B) from 5% to 95% B over 1.5 min; flow rate 4.5 mL/min,         detection at 215 nm.     -   LC-MS 3: Analytical HPLC on a Zorbax® SB-AQ column (4.6×50 mm,         3.5 μm, Agilent); Linear gradient of water/0.04% TFA (A) and         MeCN (B) from 5% to 95% B over 1.5 min; flow rate 4.5 mL/min,         detection at 215 nm.     -   LC-MS 4: Analytical HPLC on a Waters Atlantis T3 column (4.6×30         mm, 5 urn, Waters); Linear gradient of water/0.04% TFA (A) and         MeCN (B) from 5% to 95% B over 1.5 min; flow rate 4.5 mL/min,         detection at 215 nm.     -   LC-MS 5: Analytical HPLC on a Supelco Ascentis Express C18         column (5×2.1 mm, 2.7 μm, Supelco); Linear gradient of         water/0.05% formic acid (A) and MeCN (B) from 5% to 95% B over         2.5 min; flow rate 1.8 mL/min, detection at 214 and 254 nm.

Preparative HPLC/MS purifications are performed on a Gilson HPLC system, equipped with a Gilson 215 autosampler, Gilson 333/334 pumps, Finnigan AQA MS detector system, and a Dionex UV detector, using a Waters Xbridge C18 or an Waters Atlantis column, with a linear gradient of water/formic acid 0.02% (A) and MeCN (B) (acidic conditions) or water/ammonia 0.02% (A) and MeCN (B) (basic conditions).

¹H-NMR spectra are recorded either on a Varian Mercury 300VX FT-NMR spectrometer or on a Bruker Advance II 400 spectometer. All spectra were recorded at r.t., unless otherwise stated. Chemical shifts (δ) are reported in parts per million (ppm) relative to proton resonances resulting from incomplete deuteration of the NMR solvent, e.g. for DMSO δ(H) 2.49 ppm, and the abbreviations s, d, t, q, m and br refer to singlet, doublet, triplet, quartet, multiplet, and broad, respectively. Coupling constant J are given in Hz.

Synthesis of Compounds of Formula (I):

The following examples illustrate the preparation of compounds of the invention but do not at all limit the scope thereof. First the synthesis of Example compounds of Formula (I) is described, followed by the description of the synthesis of intermediates and starting materials. Whenever used in the experimental part, generic Structures 1, 2, 3 etc. refer to the respective Structures described in preceeding general description of the preparation of compounds of Formula (I).

General Method for the Preparation of Compounds of Formula (I): Saponification

To a solution of an ester of Structure 1 (0.10 mmol, 1 eq.) in THF (0.5 mL), 1M aq. NaOH (0.13 mL) was added. The resulting solution was stirred at r.t. for 14 hours. The org. solvent was removed in vacuo. The residue was diluted with water (2 mL) and acidified with 1M aq. HCl. The mixture was extracted with DCM (3×5 mL). The comb. org. phases were concentrated in vacuo. The crude product was purified by prep. HPLC (column: Waters X-Bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the desired acid as a white solid. Listed in Table 1 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding compound of Structure 1 as starting material.

TABLE 1 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 1 (±)-1-(2-Carboxymethoxy-5-fluoro- C25H22 0.87 436.2 phenyl)-3,4-dihydro-1H- NO5F LC-MS 1FA isoquinoline-2-carboxylic acid 435.25 benzyl ester 2 1-[2-((S)-1-Carboxy-ethoxy)-5- C26H24 0.90 450.2 fluoro-phenyl]-3,4-dihydro-1H- NO5F LC-MS 1FA isoquinoline-2-carboxylic acid 449.48 benzyl ester 3 (±)-1-(2-Carboxymethoxy-5- C26H25 0.90 432.2 methyl-phenyl)-3,4-dihydro-1H- NO5 LC-MS 1FA isoquinoline-2-carboxylic acid 431.49 benzyl ester 4 (±)-1-(5-Bromo-2- C25H22 0.92 496.0 carboxymethoxy-phenyl)-3,4- NO5Br LC-MS 1FA dihydro-1H-isoquinoline-2- 496.36 carboxylic acid benzyl ester 5 (±)-7-Bromo-1-(2- C25H21 0.91 514.0 carboxymethoxy-5-fluoro-phenyl)- NO5BrF LC-MS 1FA 3,4-dihydro-1H-isoquinoline-2- 514.35 carboxylic acid benzyl ester 6 (±)-1-(2-Carboxymethoxy-4,5- C25H21 0.88 454.1 difluoro-phenyl)-3,4-dihydro-1H- NO5F2 LC-MS 1FA isoquinoline-2-carboxylic acid 453.44 benzyl ester 7 (±)-5-Bromo-1-(2- C25H21 0.94 514.0 carboxymethoxy-5-fluoro-phenyl)- NO5BrF LC-MS 1FA 3,4-dihydro-1H-isoquinoline-2- 514.35 carboxylic acid benzyl ester 8 1-[2-((R)-1-Carboxy-ethoxy)-5- C26H24 0.90 450.2 fluoro-phenyl]-3,4-dihydro-1H- NO5F LC-MS 1FA isoquinoline-2-carboxylic acid 449.48 benzyl ester 9 (±)-1-(2-Carboxymethoxy-5-fluoro- C25H20 0.88 472.1 phenyl)-6,7-difluoro-3,4-dihydro- NO5F3 LC-MS 1FA 1H-isoquinoline-2-carboxylic acid 471.43 benzyl ester 10 (±)-1-(5-Bromo-2- C25H20 0.93 532.0 carboxymethoxy-phenyl)-6,7- NO5BrF2 LC-MS 1FA difluoro-3,4-dihydro-1H- 532.34 isoquinoline-2-carboxylic acid benzyl ester 11 (±)-1-(2-Carboxymethoxy-5- C26H20 0.82 479.1 cyano-phenyl)-6,7-difluoro-3,4- N2O5F2 LC-MS 1FA dihydro-1H-isoquinoline-2- 478.45 carboxylic acid benzyl ester 12 (±)-1-(2-Carboxymethoxy-5-fluoro- C26H21 0.93 504.1 phenyl)-5-trifluoromethyl-3,4- NO5F4 LC-MS 1FA dihydro-1H-isoquinoline-2- 503.45 carboxylic acid benzyl ester 13 1-[2-((R)-1-Carboxy-ethoxy)-5- C27H24 0.85 457.1 cyano-phenyl]-3,4-dihydro-1H- N2O5 LC-MS 1FA isoquinoline-2-carboxylic acid 456.50 benzyl ester 14 (±)-1-(2-Carboxymethoxy-5-fluoro- C25H20 0.89 472.1 phenyl)-5,6-difluoro-3,4-dihydro- NO5F3 LC-MS 1FA 1H-isoquinoline-2-carboxylic acid 471.43 benzyl ester 15 (±)-1-(2-Carboxymethoxy-5- C25H20 0.93 488.1 chloro-phenyl)-5,6-difluoro-3,4- NO5ClF2 LC-MS 1FA dihydro-1H-isoquinoline-2- 487.89 carboxylic acid benzyl ester 16 (±)-1-(2-Carboxymethoxy-5- C26H20 0.84 479.1 cyano-phenyl)-5,6-difluoro-3,4- N2O5F2 LC-MS 1FA dihydro-1H-isoquinoline-2- 478.45 carboxylic acid benzyl ester 17 (±)-1-(2-Carboxymethoxy-5- C27H28 0.80 525.1 dimethylsulfamoyl-phenyl)-3,4- N2O7S LC-MS 1FA dihydro-1H-isoquinoline-2- 524.59 carboxylic acid benzyl ester 18 (±)-1-(2-Carboxymethoxy-5- C25H21 0.92 470.1 chloro-phenyl)-5-fluoro-3,4- NO5ClF LC-MS 1FA dihydro-1H-isoquinoline-2- 469.90 carboxylic acid benzyl ester 19 (±)-1-(2-Carboxymethoxy-5- C26H21 0.83 461.1 cyano-phenyl)-5-fluoro-3,4- N2O5F LC-MS 1FA dihydro-1H-isoquinoline-2- 460.46 carboxylic acid benzyl ester 20 (±)-1-(2-Carboxymethoxy-5- C26H22 0.91 486.1 trifluoromethyl-phenyl)-3,4- NO5F3 LC-MS 1FA dihydro-1H-isoquinoline-2- 485.46 carboxylic acid benzyl ester 21 (±)-1-(2-Carboxymethoxy-5- C25H22 0.91 452.1 chloro-phenyl)-3,4-dihydro-1H- NO5Cl LC-MS 1FA isoquinoline-2-carboxylic acid 451.91 benzyl ester 22 (±)-1-(2-Carboxymethoxy-5- C28H29 0.96 460.2 isopropyl-phenyl)-3,4-dihydro-1H- NO5 LC-MS 1FA isoquinoline-2-carboxylic acid 459.54 benzyl ester 23 (±)-1-(6-Carboxymethoxy- C26H23 0.85 462.1 benzo[1,3]dioxol-5-yl)-3,4-dihydro- NO7 LC-MS 1FA 1H-isoquinoline-2-carboxylic acid 461.47 benzyl ester 24 (±)-1-(2-Carboxymethoxy-5- C26H25 0.85 448.2 methoxy-phenyl)-3,4-dihydro-1H- NO6 LC-MS 1FA isoquinoline-2-carboxylic acid 447.49 benzyl ester 25 (S)-1-(2-Carboxymethoxy-5- C26H22 0.81 443.2 cyano-phenyl)-3,4-dihydro-1H- N2O5 LC-MS 1FA isoquinoline-2-carboxylic acid 442.47 benzyl ester 26 (S)-1-(2-Carboxymethoxy-5- C25H22 0.91 452.1 chloro-phenyl)-3,4-dihydro-1H- NO5Cl LC-MS 1FA isoquinoline-2-carboxylic acid 451.91 benzyl ester 27 (S)-1-[2-((R)-1-Carboxy-ethoxy)-5- C26H24 0.90 450.1 fluoro-phenyl]-3,4-dihydro-1H- NO5F LC-MS 1FA isoquinoline-2-carboxylic acid 449.48 benzyl ester 28 (S)-1-[2-((S)-1-Carboxy-ethoxy)-5- C26H24 0.89 450.2 fluoro-phenyl]-3,4-dihydro-1H- NO5F LC-MS 1FA isoquinoline-2-carboxylic acid 449.48 benzyl ester 29 {4-Fluoro-2-[(S)-2-((trans)-2- C27H24 0.85 446.2 phenyl-cyclopropanecarbonyl)- NO4F LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 445.49 yl]-phenoxy}-acetic acid (diastereoisomer 1) 30 {4-Fluoro-2-[(S)-2-((trans)-2- C27H24 0.85 446.2 phenyl-cyclopropanecarbonyl)- NO4F LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 445.49 yl]-phenoxy}-acetic acid (diastereoisomer 2) 31 (S)-1-(2-Carboxymethoxy-5- C25H21 0.92 470.1 chloro-phenyl)-5-fluoro-3,4- NO5ClF LC-MS 1FA dihydro-1H-isoquinoline-2- 469.90 carboxylic acid benzyl ester 32 (S)-1-(2-Carboxymethoxy-5- C26H21 0.83 461.2 cyano-phenyl)-5-fluoro-3,4- N2O5F LC-MS 1FA dihydro-1H-isoquinoline-2- 460.46 carboxylic acid benzyl ester

Phenol Alkylation and Subsequent Saponification

To a solution of a phenol 13 (0.20 mmol, 1.0 eq.) and K₂CO₃ (83 mg, 0.60 mmol, 3.0 eq.) in DMF (1 mL), ethyl bromoacetate (33 μL, 0.30 mmol, 1.5 eq.) was added. The reaction mixture was stirred at r.t. for 5 hours. 1M aq. NaOH (0.5 mL) was added. The mixture was stirred at r.t. for 89 hours. The solution was carefully neutralized with formic acid (0.5 mL), filtered, and purified by prep. HPLC (column: Waters X-bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) to give the desired acid as a white solid.

Listed in Table 2 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding phenol 13 as starting material.

TABLE 2 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H ]⁺ 33 (±)-1-(2-Carboxymethoxy-3,5- C25H21 0.87 454.1 difluoro-phenyl)-3,4-dihydro-1H- NO5F2 LC-MS 1FA isoquinoline-2-carboxylic acid 453.44 benzyl ester 34 (±)-1-(2-Carboxymethoxy-5-fluoro- C25H21 0.88 454.1 phenyl)-5-fluoro-3,4-dihydro-1H- NO5F2 LC-MS 1FA isoquinoline-2-carboxylic acid 453.44 benzyl ester 35 (±)-1-(2-Carboxymethoxy-5-fluoro- C26H24 0.89 466.2 phenyl)-5-methoxy-3,4-dihydro- NO6F LC-MS 1FA 1H-isoquinoline-2-carboxylic acid 465.48 benzyl ester 36 (±)-1-(2-Carboxymethoxy-5-fluoro- C27H26 0.82 496.2 phenyl)-6,7-dimethoxy-3,4- NO7F LC-MS 1FA dihydro-1H-isoquinoline-2- 495.50 carboxylic acid benzyl ester 37 (±)-1-(2-Carboxymethoxy-5-fluoro- C26H24 0.86 466.1 phenyl)-7-methoxy-3,4-dihydro- NO6F LC-MS 1FA 1H-isoquinoline-2-carboxylic acid 465.48 benzyl ester 38 (±)-1-(2-Carboxymethoxy-5-fluoro- C25H21 0.93 470.1 phenyl)-5-chloro-3,4-dihydro-1H- NO5ClF LC-MS 1FA isoquinoline-2-carboxylic acid 469.90 benzyl ester 39 (±)-1-(2-Carboxymethoxy-5-fluoro- C26H24 0.91 450.1 phenyl)-5-methyl-3,4-dihydro-1H- NO5F LC-MS 1FA isoquinoline-2-carboxylic acid 449.48 benzyl ester 40 (±)-5-Bromo-1-(2- C25H20 0.94 532.0 carboxymethoxy-5-fluoro-phenyl)- NO5BrF2 LC-MS 1FA 6-fluoro-3,4-dihydro-1H- 532.34 isoquinoline-2-carboxylic acid benzyl ester 41 (±)-1-(2-Carboxymethoxy-5-fluoro- C25H21 0.87 454.1 phenyl)-7-fluoro-3,4-dihydro-1H- NO5F2 LC-MS 1FA isoquinoline-2-carboxylic acid 453.44 benzyl ester 42 (±)-1-(2-Carboxymethoxy-5-fluoro- C25H20 0.89 472.1 phenyl)-5,7-difluoro-3,4-dihydro- NO5F3 LC-MS 1FA 1H-isoquinoline-2-carboxylic acid 471.43 benzyl ester 43 (±)-1-(2-Carboxymethoxy-5- C25H20 0.93 488.1 chloro-phenyl)-5,7-difluoro-3,4- NO5ClF2 LC-MS 1FA dihydro-1H-isoquinoline-2- 487.89 carboxylic acid benzyl ester 44 (±)-1-(2-Carboxymethoxy-5- C26H20 0.84 479.1 cyano-phenyl)-5,7-difluoro-3,4- N2O5F2 LC-MS 1FA dihydro-1H-isoquinoline-2- 478.45 carboxylic acid benzyl ester

Amide Coupling and Subsequent Saponification

Method A: To a solution of 2-(1,2-benzisoxazol-3-yl)acetic acid (20 mg, 0.10 mmol, 1.0 eq.) in DMF (0.5 mL), TBTU (32 mg, 0.10 mmol, 1.0 eq.) and Si-DEA (400 mg, 0.50 mmol, 5.0 eq.) were added. The resulting mixture was stirred at r.t. for 5 min. A solution of (±)-[4-fluoro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (44 mg, 0.12 mmol, 1.2 eq.) in DCM (1 mL) was added. The mixture was stirred at r.t. for 18 hours. The resulting suspension was filtered, the solids were rinsed with DCM (5 mL), and the filtrate was concentrated in vacuo. The residue was dissolved in THF (1 mL) and 0.2M aq. NaOH (1 mL) was added. The mixture was stirred at r.t. for 30 min. The mixture was neutralized with 0.2M aq. HCl soln. and concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters X-Bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the desired acid as a white solid.

Listed in Table 3 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding amine of Structure 2 and the corresponding acid as starting materials.

TABLE 3 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 45 (±)-{2-[2-(2-Benzo[d]isoxazol-3-yl- C26H21 0.80 461.1 acetyl)-1,2,3,4-tetrahydro- N2O5F LC-MS 1FA isoquinolin-1-yl]-4-fluoro- 460.46 phenoxy}-acetic acid 46 (±)-{4-Fluoro-2-[2-(3-methyl-3- C28H28 0.90 462.2 phenyl-butyryl)-1,2,3,4-tetrahydro- NO4F LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 461.53 acid 47 (±)-{4-Fluoro-2-[2-(2-naphthalen- C29H24 0.87 470.2 1-yl-acetyl)-1,2,3,4-tetrahydro- NO4F LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 469.51 acid 48 (±)-{4-Fluoro-2-[2-(2-quinolin-7-yl- C28H23 0.61 471.2 acetyl)-1,2,3,4-tetrahydro- N2O4F LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 470.50 acid 49 (±)-{4-Fluoro-2-[2-(2-quinolin-6-yl- C28H23 0.62 471.2 acetyl)-1,2,3,4-tetrahydro- N2O4F LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 470.50 acid 50 (±)-{2-[2-(2-2,3-Dihydro- C27H24 0.78 478.1 benzo[1,4]dioxin-6-yl-acetyl)- NO6F LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 477.49 yl]-4-fluoro-phenoxy}-acetic acid 51 (±)-{4-Fluoro-2-[2-(3-1H-indol-3-yl- C28H25 0.81 473.2 propionyl)-1,2,3,4-tetrahydro- N2O4F LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 472.51 acid 52 (±)-(2-{2-[3-(1-Ethyl-2-methyl-1H- C31H31 0.92 515.2 indol-3-yl)-propionyl]-1,2,3,4- N2O4F LC-MS 1FA tetrahydro-isoquinolin-1-yl}-4- 514.60 fluoro-phenoxy)-acetic acid 53 (±)-(2-{2-[3-(2,6-Dichloro-phenyl)- C26H22 0.91 502.1 propionyl]-1,2,3,4-tetrahydro- NO4Cl2F LC-MS 1FA isoquinolin-1-yl}-4-fluoro- 502.37 phenoxy)-acetic acid 54 (±)-(4-Fluoro-2-{2-[3-(2-fluoro- C26H23 0.84 468.1 phenoxy)-propionyl]-1,2,3,4- NO5F2 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 467.47 phenoxy)-acetic acid 55 (±)-[4-Fluoro-2-(2-{2-[4-(5-methyl- C27H24 0.73 502.2 tetrazol-1-yl)-phenyl]-acetyl}- N5O4F LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 501.52 yl)-phenoxy]-acetic acid 56 (±)-(2-{2-[3-(6-Chloro-3-oxo-2,3- C28H24 0.83 539.1 dihydro-benzo[1,4]oxazin-4-yl)- N2O6ClF LC-MS 1FA propionyl]-1,2,3,4-tetrahydro- 538.96 isoquinolin-1-yl}-4-fluoro- phenoxy)-acetic acid 57 (±)-(4-Fluoro-2-{2-[2-(2-methyl- C23H21 0.73 441.1 thiazol-4-yl)-acetyl]-1,2,3,4- N2O4FS LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 440.49 phenoxy)-acetic acid 58 (±)-{2-[2-(2-Benzo[b]thiophen-3-yl- C27H22 0.87 476.1 acetyl)-1,2,3,4-tetrahydro- NO4FS LC-MS 1FA isoquinolin-1-yl]-4-fluoro- 475.54 phenoxy}-acetic acid 59 (±)-{2-[2-(3-Benzothiazol-2-yl- C27H23 0.83 491.1 propionyl)-1,2,3,4-tetrahydro- N2O4FS LC-MS 1FA isoquinolin-1-yl]-4-fluoro- 490.55 phenoxy}-acetic acid 60 (±)-{2-[2-(2-Biphenyl-4-yl-acetyl)- C31H26 0.92 496.2 1,2,3,4-tetrahydro-isoquinolin-1- NO4F LC-MS 1FA yl]-4-fluoro-phenoxy}-acetic acid 495.55 61 (±)-{4-Fluoro-2-[2-(2-indol-1-yl- C27H23 0.83 459.2 acetyl)-1,2,3,4-tetrahydro- N2O4F LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 458.49 acid 62 (±)-{2-[2-(2-1H-Benzoimidazol-2- C26H22 0.57 460.2 yl-acetyl)-1,2,3,4-tetrahydro- N3O4F LC-MS 1FA isoquinolin-1-yl]-4-fluoro- 459.48 phenoxy}-acetic acid 63 (±)-{2-[2-(2-1,3-Dihydro-isoindol-2- C27H25 0.64 461.2 yl-acetyl)-1,2,3,4-tetrahydro- N2O4F LC-MS isoquinolin-1-yl]-4-fluoro- 460.50 1TFA phenoxy}-acetic acid 64 (±)-(4-Fluoro-2-{2-[3-(5-methoxy- C29H27 0.79 503.2 1H-indol-3-yl)-propionyl]-1,2,3,4- N2O5F LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 502.54 phenoxy)-acetic acid 65 (±)-(4-Fluoro-2-{2-[3-(2-methyl-1H- C29H27 0.83 487.2 indol-3-yl)-propionyl]-1,2,3,4- N2O4F LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 486.54 phenoxy)-acetic acid 66 (±)-(4-Fluoro-2-{2-[3-(1-methyl-1H- C29H27 0.87 487.2 indol-3-yl)-propionyl]-1,2,3,4- N2O4F LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 486.54 phenoxy)-acetic acid 67 (±)-{4-Fluoro-2-[2-(trans-2-phenyl- C27H24 0.85 446.2 cyclopropanecarbonyl)-1,2,3,4- NO4F LC-MS 1FA tetrahydro-isoquinolin-1-yl]- 445.49 phenoxy}-acetic acid 68 (±)-{4-Chloro-2-[2-(2-cyclopropyl- C22H22 0.81 400.1 acetyl)-1,2,3,4-tetrahydro- NO4Cl LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 399.87 acid 69 (±)-{4-Chloro-2-[2-(2H-chromene- C27H22 0.88 476.1 3-carbonyl)-1,2,3,4-tetrahydro- NO5Cl LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 475.93 acid 70 (±)-{4-Chloro-2-[2-(3-methoxy- C21H22 0.75 404.1 propionyl)-1,2,3,4-tetrahydro- NO5Cl LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 403.86 acid 71 (±)-(4-Chloro-2-{2-[2-(2-chloro- C25H21 0.88 470.0 phenyl)-acetyl]-1,2,3,4-tetrahydro- NO4Cl2 LC-MS 1FA isoquinolin-1-yl}-phenoxy)-acetic 470.35 acid 72 (±)-{4-Chloro-2-[2-(2-indol-1-yl- C27H23 0.87 475.1 acetyl)-1,2,3,4-tetrahydro- N2O4 Cl LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 474.94 acid 73 (±)-(4-Chloro-2-{2-[3-(2-methyl- C29H27 0.86 503.1 1H-indol-3-yl)-propionyl]-1,2,3,4- N2O4 Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 503.00 phenoxy)-acetic acid 74 (±)-(4-Chloro-2-{2-[3-(5-methoxy- C29H27 0.83 519.2 1H-indol-3-yl)-propionyl]-1,2,3,4- N2O5 Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 519.00 phenoxy)-acetic acid 75 (±)-(4-Chloro-2-{2-[2-(2,6- C26H25 0.58 481.1 dimethyl-pyridin-3-yloxy)-acetyl]- N2O5 Cl LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 480.95 yl}-phenoxy)-acetic acid 76 (±)-(4-Chloro-2-{2-[3-(1-methyl- C29H27 0.91 503.2 1H-indol-3-yl)-propionyl]-1,2,3,4- N2O4 Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 503.00 phenoxy)-acetic acid 77 {4-Chloro-2-[2-(1,2,3,4-tetrahydro- C28H26 0.93 476.1 naphthalene-2-carbonyl)-1,2,3,4- NO4Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl]- 475.97 phenoxy}-acetic acid 78 (±)-{2-[2-(2-Benzoimidazol-1-yl- C26H22 0.63 476.1 acetyl)-1,2,3,4-tetrahydro- N3O4Cl LC-MS 1FA isoquinolin-1-yl]-4-chloro- 475.93 phenoxy}-acetic acid 79 (±)-{4-Chloro-2-[2-(2-3,4-dihydro- C28H27 0.91 491.2 2H-quinolin-1-yl-acetyl)-1,2,3,4- N2O4Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl]- 490.99 phenoxy}-acetic acid 80 (±)-{4-Chloro-2-[2-(2-indazol-2-yl- C26H22 0.80 476.1 acetyl)-1,2,3,4-tetrahydro- N3O4 Cl LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 475.93 acid 81 (±)-(4-Chloro-2-{2-[3-(3- C27H23 0.93 518.1 trifluoromethyl-phenyl)-propionyl]- NO4ClF3 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 517.93 yl}-phenoxy)-acetic acid 82 (4-Chloro-2-{2-[trans-2-(2-chloro- C27H23 0.91 496.1 phenyl)-cyclopropanecarbonyl]- NO4Cl2 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 496.39 yl}-phenoxy)-acetic acid 83 (±)-(4-Chloro-2-{2-[3-(1-phenyl- C29H26 0.64 516.2 1H-imidazol-2-yl)-propionyl]- N3O4Cl LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 516.00 yl}-phenoxy)-acetic acid 84 (4-Chloro-2-{2-[3-(4-oxo-2-phenyl- C29H27 0.84 551.2 thiazolidin-3-yl)-propionyl]-1,2,3,4- N2O5ClS LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 551.06 phenoxy)-acetic acid 85 (±)-[4-Chloro-2-(2-{3-[3-(2,3- C31H30 0.66 544.2 dimethyl-phenyl)-3H-imidazol-4- N3O4Cl LC-MS 1FA yl]-propionyl}-1,2,3,4-tetrahydro- 544.05 isoquinolin-1-yl)-phenoxy]-acetic acid 86 (±)-(2-{2-[2-(Biphenyl-2-yloxy)- C31H26 0.95 528.2 acetyl]-1,2,3,4-tetrahydro- NO5Cl LC-MS 1FA isoquinolin-1-yl}-4-chloro- 528.00 phenoxy)-acetic acid 87 (±)-(4-Chloro-2-{2-[3-(3-fluoro- C26H23 0.88 484.1 phenoxy)-propionyl]-1,2,3,4- NO5ClF LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 483.92 phenoxy)-acetic acid 88 (±)-{4-Chloro-2-[2-(3-p-tolyloxy- C27H26 0.91 480.1 propionyl)-1,2,3,4-tetrahydro- NO5Cl LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 479.96 acid 89 (±)-(4-Chloro-2-{2-[3-(4-chloro- C26H23 0.92 500.1 phenoxy)-propionyl]-1,2,3,4- NO5Cl2 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 500.38 phenoxy)-acetic acid 90 (±)-(4-Chloro-2-{2-[3-(2- C27H23 0.93 518.1 trifluoromethyl-phenyl)-propionyl]- NO4ClF3 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 517.93 yl}-phenoxy)-acetic acid 91 (±)-(4-Chloro-2-{2-[2-(5-fluoro-1H- C27H22 0.82 493.1 indol-3-yl)-acetyl]-1,2,3,4- N2O4ClF LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 492.93 phenoxy)-acetic acid 92 (±)-(4-Chloro-2-{2-[2-(6-methoxy- C28H24 0.87 506.1 benzofuran-3-yl)-acetyl]-1,2,3,4- NO6Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 505.95 phenoxy)-acetic acid 93 (±)-(4-Chloro-2-{2-[4-(4-chloro- C27H25 0.95 498.1 phenyl)-butyryl]-1,2,3,4- NO4Cl2 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 498.41 phenoxy)-acetic acid 94 (±)-{4-Chloro-2-[2-(3-m-tolyloxy- C27H26 0.91 480.1 propionyl)-1,2,3,4-tetrahydro- NO5Cl LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 479.96 acid 95 (±)-(4-Chloro-2-{2-[3-(3-chloro- C26H23 0.92 500.1 phenoxy)-propionyl]-1,2,3,4- NO5Cl2 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 500.38 phenoxy)-acetic acid 96 (±)-(4-Chloro-2-{2-[2-(5-chloro-1H- C27H22 0.86 509.1 indol-3-yl)-acetyl]-1,2,3,4- N2O4Cl2 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 509.39 phenoxy)-acetic acid 97 (±)-{4-Chloro-2-[2-(4-p-tolyl- C28H28 0.95 478.2 butyryl)-1,2,3,4-tetrahydro- NO4Cl LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 477.99 acid 98 (±)-(4-Chloro-2-{2-[2-(5-chloro- C27H21 0.94 526.0 benzo[b]thiophen-3-yl)-acetyl]- NO4Cl2S LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 526.44 yl}-phenoxy)-acetic acid 99 (±)-(4-Chloro-2-{2-[2-(5-methoxy- C28H25 0.83 505.1 1H-indol-2-yl)-acetyl]-1,2,3,4- N2O5Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 504.97 phenoxy)-acetic acid 100 (±)-(4-Chloro-2-{2-[2-(5-methyl- C27H23 0.87 491.1 benzo[d]isoxazol-3-yl)-acetyl]- N2O5Cl LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 490.94 yl}-phenoxy)-acetic acid 101 (±)-(4-Chloro-2-{2-[2-(5-methoxy- C27H23 0.84 507.1 benzo[d]isoxazol-3-yl)-acetyl]- N2O6Cl LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 506.94 yl}-phenoxy)-acetic acid 102 (±)-(4-Chloro-2-{2-[3-(4-fluoro- C26H23 0.88 484.1 phenoxy)-propionyl]-1,2,3,4- NO5ClF LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 483.92 phenoxy)-acetic acid 103 (±)-(4-Chloro-2-{2-[4-(4-fluoro- C27H25 0.91 482.1 phenyl)-butyryl]-1,2,3,4- NO4ClF LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 481.95 phenoxy)-acetic acid

Method B: To a solution of 2-methylhydrocinnamic acid (12 mg, 0.08 mmol, 1.5 eq.) in DMF (1 mL), DIPEA (34 μL, 0.20 mmol, 4.0 eq.), and TBTU (24 mg, 0.08 mmol, 1.5 eq.) were added in sequence. The resulting solution was stirred at r.t. for 30 min. Then (±)-[4-chloro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester (17 mg, 0.05 mmol, 1.0 eq.) was added and the resulting mixture was stirred at r.t. for 18 hours. 1M aq. NaOH (0.50 mL) was added. The mixture was stirred at r.t. for 2 hours. The solution was neutralized with formic acid (0.50 mL), filtered, and then purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) to give the desired acid as a white solid.

Listed in Table 4 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding amine of Structure 2 and the corresponding acid as starting materials.

TABLE 4 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 104 (±)-{4-Chloro-2-[2-(3-o-tolyl- C27H26 0.91 464.1 propionyl)-1,2,3,4-tetrahydro- NO4Cl LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 463.96 acid 105 (±)-{2-[2-(2-Benzyloxy-acetyl)- C26H24 0.85 466.1 1,2,3,4-tetrahydro-isoquinolin-1- NO5Cl LC-MS 1FA yl]-4-chloro-phenoxy}-acetic acid 465.93 106 (±)-(4-Chloro-2-{2-[2-(2-chloro- C26H23 0.89 500.1 benzyloxy)-acetyl]-1,2,3,4- NO5Cl2 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 500.38 phenoxy)-acetic acid 107 (±)-{4-Chloro-2-[2-(4-phenyl- C27H26 0.91 464.1 butyryl)-1,2,3,4-tetrahydro- NO4Cl LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 463.96 acid 108 (±)-(4-Chloro-2-{2-[4-(3-fluoro- C27H25 0.92 482.1 phenyl)-butyryl]-1,2,3,4- NO4ClF LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 481.95 phenoxy)-acetic acid 109 (±)-(4-Chloro-2-{2-[4-(2,3-dichloro- C27H24 0.98 532.0 phenyl)-butyryl]-1,2,3,4- NO4Cl3 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 532.85 phenoxy)-acetic acid 110 (±)-{4-Chloro-2-[2-(4-m-tolyl- C28H28 0.95 478.1 butyryl)-1,2,3,4-tetrahydro- NO4Cl LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 477.99 acid 111 (±)-{4-Chloro-2-[2-(4-o-tolyl- C28H28 0.94 478.2 butyryl)-1,2,3,4-tetrahydro- NO4Cl LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 477.99 acid 112 (±)-(4-Chloro-2-{2-[4-(3-chloro- C27H25 0.95 498.1 phenyl)-butyryl]-1,2,3,4- NO4Cl2 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 498.41 phenoxy)-acetic acid 113 (±)-(4-Chloro-2-{2-[4-(2-chloro- C27H25 0.95 498.1 phenyl)-butyryl]-1,2,3,4- NO4Cl2 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 498.41 phenoxy)-acetic acid 114 (±)-(4-Chloro-2-{2-[4-(3-methoxy- C28H28 0.90 494.2 phenyl)-butyryl]-1,2,3,4- NO5Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 493.99 phenoxy)-acetic acid 115 (±)-(4-Chloro-2-{2-[4-(2-fluoro- C27H25 0.92 482.1 phenyl)-butyryl]-1,2,3,4- NO4ClF LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 481.95 phenoxy)-acetic acid 116 (±)-{4-Chloro-2-[2-(trans-2-phenyl- C27H24 0.88 462.1 cyclopropanecarbonyl)-1,2,3,4- NO4Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl]- 461.94 phenoxy}-acetic acid 117 {4-Chloro-2-[5-fluoro-2-(trans-2- C27H23 0.90 480.1 phenyl-cyclopropanecarbonyl)- NO4ClF LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 479.93 yl]-phenoxy}-acetic acid 118 (±)-{4-Chloro-2-[5-fluoro-2-(3-o- C27H25 0.92 482.1 tolyl-propionyl)-1,2,3,4-tetrahydro- NO4ClF LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 481.95 acid 119 (±)-{2-[2-(2-Benzyloxy-acetyl)-5- C26H23 0.86 484.1 fluoro-1,2,3,4-tetrahydro- NO5ClF LC-MS 1FA isoquinolin-1-yl]-4-chloro- 483.92 phenoxy}-acetic acid 120 (±)-(4-Chloro-2-{2-[2-(2-chloro- C26H22 0.90 518.0 benzyloxy)-acetyl]-5-fluoro- NO5Cl2F LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 518.37 yl}-phenoxy)-acetic acid 121 (±)-{4-Chloro-2-[5-fluoro-2-(4- C27H25 0.93 482.1 phenyl-butyryl)-1,2,3,4-tetrahydro- NO4ClF LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 481.95 acid 122 (±)-{4-Chloro-2-[5-fluoro-2-(3- C26H19 0.90 464.1 phenyl-propynoyl)-1,2,3,4- NO4ClF LC-MS 1FA tetrahydro-isoquinolin-1-yl]- 463.89 phenoxy}-acetic acid

Method C: To a solution of 3-phenylpropionic acid (23 mg, 0.16 mmol, 1.1 eq.) in DMF/THF (4:1, 1 mL), HATU (108 mg, 0.28 mmol, 2.0 eq.) and DIPEA (49 μL, 0.28 mmol, 2.0 eq.) were added. The mixture was stirred at r.t. for 30 min. A solution of (±)-[4-fluoro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (51 mg, 0.14 mmol, 1.0 eq.) and DIPEA (49 μL, 0.28 mmol, 2.0 eq.) in DMF/THF (4:1, 1 mL) was added at 0° C. The mixture was stirred at r.t. for 18 hours. The reaction mixture was diluted with DCM and washed with sat. aq. NaHCO₃ soln. and water. The org. phase was concentrated in vacuo. The residue was dissolved in THF (2 mL) and 1M aq. NaOH soln. (2 mL) was added. The mixture was stirred at r.t. for 5 hours. The mixture was acidified with acetic acid (pH<5). Water (2 mL) and DCM (2 mL) were added. The layers were separated and the org. phase was concentrated in vacuo. The residue was purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) to give the desired acid as a white solid.

Listed in Table 5 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding amine of Structure 2 and the corresponding acid as starting materials.

TABLE 5 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 123 (±)-{4-Fluoro-2-[2-(3-phenyl- C26H24 0.84 434.2 propionyl)-1,2,3,4-tetrahydro- NO4F LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 433.48 acid 124 (±)-[4-Fluoro-2-(2-phenylacetyl- C25H22 0.81 420.2 1,2,3,4-tetrahydro-isoquinolin-1- NO4F LC-MS 1FA yl)-phenoxy]-acetic acid 419.45 125 (±)-{4-Fluoro-2-[2-(2-phenoxy- C25H22 0.80 436.1 acetyl)-1,2,3,4-tetrahydro- NO5F LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 435.45 acid 126 (±)-{2-[2-(2-Benzyloxy-acetyl)- C26H24 0.81 450.1 1,2,3,4-tetrahydro-isoquinolin-1- NO5F LC-MS 1FA yl]-4-fluoro-phenoxy}-acetic acid 449.48 127 (±)-{4-Fluoro-2-[2-(4-phenyl- C27H26 0.88 448.2 butyryl)-1,2,3,4-tetrahydro- NO4F LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 447.50 acid 128 (±)-(4-Fluoro-2-{2-[3-(2-methoxy- C27H26 0.86 464.1 phenyl)-propionyl]-1,2,3,4- NO5F LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 463.50 phenoxy)-acetic acid 129 (±)-(4-Fluoro-2-{2-[3-(3-methoxy- C27H26 0.84 464.2 phenyl)-propionyl]-1,2,3,4- NO5F LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 463.50 phenoxy)-acetic acid 130 (±)-(4-Fluoro-2-{2-[3-(4-methoxy- C27H26 0.83 464.2 phenyl)-propionyl]-1,2,3,4- NO5F LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 463.50 phenoxy)-acetic acid 131 (±)-(2-{2-[3-(2-Chloro-phenyl)- C26H23 0.88 468.1 propionyl]-1,2,3,4-tetrahydro- NO4ClF LC-MS 1FA isoquinolin-1-yl}-4-fluoro- 467.92 phenoxy)-acetic acid 132 (±)-(2-{2-[3-(3-Chloro-phenyl)- C26H23 0.89 468.1 propionyl]-1,2,3,4-tetrahydro- NO4ClF LC-MS 1FA isoquinolin-1-yl}-4-fluoro- 467.92 phenoxy)-acetic acid 133 (±)-(2-{2-[3-(4-Chloro-phenyl)- C26H23 0.89 468.1 propionyl]-1,2,3,4-tetrahydro- NO4ClF LC-MS 1FA isoquinolin-1-yl}-4-fluoro- 467.92 phenoxy)-acetic acid 134 (±)-{4-Fluoro-2-[2-(3-o-tolyl- C27H26 0.88 448.2 propionyl)-1,2,3,4-tetrahydro- NO4F LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 447.50 acid

Method D: To a suspension of (±)-[4-fluoro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (37 mg, 0.10 mmol, 1.0 eq.) in DCM (1 mL), Si-carbonate (220 mg) was added. The mixture was stirred at r.t. for 1 hour, filtered, and the filtrate was concentrated in vacuo to give the free amine.

To a solution of 2-naphthylacetic acid (28 mg, 0.15 mmol, 1.5 eq.) in DCM (1 mL), a solution of the Ghosez's reagent in DCM (0.21 mmol, 2.1 eq.) was added. The resulting mixture was stirred at r.t. for 10 min. A solution of the free amine and Si-DEA (0.45 mmol, 4.5 eq.) in DCM (0.5 mL) was added. The mixture was stirred at r.t. for 1 hour, filtered, and concentrated in vacuo. The residue was dissolved in THF (0.5 mL) and 0.2M aq. NaOH soln. was added. The mixture was stirred at r.t. for 20 min, then neutralized with 1M aq. HCl soln., and concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters X-bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) to give the desired acid as a white solid.

Listed in Table 6 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding amine of Structure 2 and the corresponding acid as starting materials.

TABLE 6 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 135 (±)-{4-Fluoro-2-[2-(2-naphthalen- C29H24 0.87 470.2 2-yl-acetyl)-1,2,3,4-tetrahydro- NO4F LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 469.51 acid 136 (±)-{4-Fluoro-2-[2-(2-o-tolyloxy- C26H24 0.85 450.2 acetyl)-1,2,3,4-tetrahydro- NO5F LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 449.48 acid 137 (±)-(4-Fluoro-2-{2-[2-(1-methyl-1H- C28H25 0.84 473.2 indol-3-yl)-acetyl]-1,2,3,4- N2O4F LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 472.51 phenoxy)-acetic acid 138 (±)-(2-{2-[2-(2-Chloro-phenoxy)- C25H21 0.84 470.1 acetyl]-1,2,3,4-tetrahydro- NO5ClF LC-MS 1FA isoquinolin-1-yl}-4-fluoro- 469.90 phenoxy)-acetic acid 139 (±)-(4-Fluoro-2-{2-[3-(2-fluoro- C26H23 0.85 452.1 phenyl)-propionyl]-1,2,3,4- NO4F2 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 451.47 phenoxy)-acetic acid 140 (±)-{4-Fluoro-2-[2-(2-indan-2-yl- C28H26 0.89 460.2 acetyl)-1,2,3,4-tetrahydro- NO4F LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 459.52 acid 141 (±)-(4-Fluoro-2-{2-[(E)-3-(2-fluoro- C26H21 0.85 450.1 phenyl)-acryloyl]-1,2,3,4- NO4F2 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 449.45 phenoxy)-acetic acid 142 (±)-{4-Fluoro-2-[2-((E)-3-o-tolyl- C27H24 0.87 446.2 acryloyl)-1,2,3,4-tetrahydro- NO4F LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 445.49 acid 143 (±)-{4-Fluoro-2-[2-(5-phenyl- C28H28 0.91 462.2 pentanoyl)-1,2,3,4-tetrahydro- NO4F LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 461.53 acid 144 (±)-{4-Fluoro-2-[2-(3-phenoxy- C26H24 0.84 450.2 propionyl)-1,2,3,4-tetrahydro- NO5F LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 449.48 acid 145 (±)-(4-Fluoro-2-{2-[3-(4- C27H26 0.73 512.1 methanesulfonyl-phenyl)- NO6FS LC-MS 1FA propionyl]-1,2,3,4-tetrahydro- 511.57 isoquinolin-1-yl}-phenoxy)-acetic acid 146 (±)-{2-[2-(3-2,3-Dihydro-indol-1-yl- C28H27 0.85 475.2 propionyl)-1,2,3,4-tetrahydro- N2O4F LC-MS 1FA isoquinolin-1-yl]-4-fluoro- 474.53 phenoxy}-acetic acid 147 (±)-{4-Fluoro-2-[2-(3-o-tolyloxy- C27H26 0.88 464.2 propionyl)-1,2,3,4-tetrahydro- NO5F LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 463.50 acid 148 (±)-(4-Fluoro-2-{2-[2-(2-fluoro- C25H21 0.81 454.1 phenoxy)-acetyl]-1,2,3,4- NO5F2 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 453.44 phenoxy)-acetic acid 149 (±)-(4-Fluoro-2-{2-[4-(2-methoxy- C28H28 0.88 478.2 phenyl)-butyryl]-1,2,3,4- NO5F LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 477.53 phenoxy)-acetic acid

Method E: To a solution of (±)-[4-fluoro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (42 mg, 0.10 mmol, 1.0 eq.) and [(2-chlorobenzyl)oxy]acetic acid (20 mg, 0.10 mmol, 1.0 eq.) in DMF (1.2 mL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (29 mg, 0.15 mmol, 1.5 eq.) and 4-(dimethylamino)pyridine (31 mg, 0.25 mmol, 2.5 eq.) were added in sequence. The mixture was stirred at r.t. for 86 hours. The mixture was diluted with AcOEt (10 mL). The diluted solution was washed with 1M aq. HCl soln. (2×5 mL), sat. aq. NaHCO₃ soln. (2×5 mL), sat. aq. NaCl soln. (1×5 mL), dried over MgSO₄, and concentrated in vacuo. The residue was dissolved in THF (0.5 mL). 1M aq. NaOH (0.28 mL) was added. The mixture was stirred at r.t. for 17 hours. The mixture was concentrated in vacuo. The residue was diluted with water (2 mL) and acidified with 1M aq. HCl soln. The mixture was extracted with DCM/THF 2:1 (3×6 mL). The comb. org. phases were concentrated in vacuo.

The residue was purified by prep. HPLC (column: Waters X-bridge, 19×50 mm, 10 um, UV/MS, acidic conditions) to give the acid as a white solid.

Listed in Table 7 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding amine of Structure 2 and the corresponding acid as starting materials.

TABLE 7 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 150 (±)-(2-{2-[2-(2-Chloro-benzyloxy)- C26H23 0.86 484.1 acetyl]-1,2,3,4-tetrahydro- NO5ClF LC-MS 1FA isoquinolin-1-yl}-4-fluoro- 483.92 phenoxy)-acetic acid 151 (±)-(4-Chloro-2-{2-[(trans)-2-(3- C27H23 0.94 496.1 chloro-phenyl)- NO4Cl2 LC-MS 1FA cyclopropanecarbonyl]-1,2,3,4- 496.39 tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid (diastereoisomer 1) 152 (±)-(4-Chloro-2-{2-[(trans)-2-(3- C27H23 0.92 496.1 chloro-phenyl)- NO4Cl2 LC-MS 1FA cyclopropanecarbonyl]-1,2,3,4- 496.39 tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid (diastereoisomer 2) 153 (±)-{4-Chloro-2-[2-((trans)-2-o- C28H26 0.93 476.2 tolyl-cyclopropanecarbonyl)- NO4Cl LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 475.97 yl]-phenoxy}-acetic acid (diastereosiomer 1) 154 (±)-{4-Chloro-2-[2-((trans)-2-o- C28H26 0.91 476.2 tolyl-cyclopropanecarbonyl)- NO4Cl LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 475.97 yl]-phenoxy}-acetic acid (diastereosiomer 2) 155 (±)-(4-Chloro-2-{2-[(trans)-2-(2- C28H23 0.93 530.2 trifluoromethyl-phenyl)- NO4ClF3 LC-MS 1FA cyclopropanecarbonyl]-1,2,3,4- 529.94 tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid (diatereoisomer 1) 156 (±)-(4-Chloro-2-{2-[(trans)-2-(2- C28H23 0.92 530.2 trifluoromethyl-phenyl)- NO4ClF3 LC-MS 1FA cyclopropanecarbonyl]-1,2,3,4- 529.94 tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid (diatereoisomer 2) 157 (±)-(4-Chloro-2-{2-[trans-2-(4- C27H23 0.93 496.1 chloro-phenyl)- NO4Cl2 LC-MS 1FA cyclopropanecarbonyl]-1,2,3,4- 496.39 tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 158 (±)-(4-Chloro-2-{2-[trans-2-(2,4- C27H22 0.97 530.0 dichloro-phenyl)- NO4Cl3 LC-MS 1FA cyclopropanecarbonyl]-1,2,3,4- 530.83 tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 159 (±)-(4-Chloro-2-{2-[trans-2-(2- C28H26 0.89 492.1 methoxy-phenyl)- NO5Cl LC-MS 1FA cyclopropanecarbonyl]-1,2,3,4- 491.97 tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 160 (±)-(4-Chloro-2-{2-[trans-2-(2- C27H23 0.88 480.1 fluoro-phenyl)- NO4ClF LC-MS 1FA cyclopropanecarbonyl]-1,2,3,4- 479.93 tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 161 (±)-(4-Chloro-2-{2-[3-(3-phenyl- C28H25 0.80 517.2 3H-[1,2,3]triazol-4-yl)-propionyl]- N4O4Cl LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 516.98 yl}-phenoxy)-acetic acid 162 (±)-(4-Chloro-2-{2-[2-(3-phenyl- C27H23 0.82 535.2 3H-[1,2,3]triazol-4-ylsulfanyl)- N4O4ClS LC-MS 1FA acetyl]-1,2,3,4-tetrahydro- 535.02 isoquinolin-1-yl}-phenoxy)-acetic acid

Carbamate Formation and Subsequent Saponification

Method A: To a solution of an (±)-[4-fluoro-2-(6-fluoro-1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester (5 mg, 0.014 mmol, 1.0 eq.) and NEt₃ (4 μL, 0.028 mmol, 2.0 eq.) in DCM (1 mL), benzyl chloroformate (2 μL, 0.016 mmol, 1.1 eq.) was added. The resulting solution was stirred at r.t. for 18 hours. The solvent was evaporated and the residue was dissolved in DMF (0.5 mL). 1M aq. NaOH (0.50 mL) was added. The mixture was stirred at r.t. for 2 hours. The solution was neutralized with formic acid (0.50 mL) and then purified by prep. HPLC (column: Atlantis, 18×50 mm, 10 um, UV/MS, acidic conditions) to give the desired acid as a white solid.

Listed in Table 8 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding amine of Structure 2 and the corresponding chloroformate as starting materials.

TABLE 8 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 163 (±)-1-(2-Carboxymethoxy-5-fluoro- C25H21 0.87 454.1 phenyl)-6-fluoro-3,4-dihydro-1H- NO5F2 LC-MS 1FA isoquinoline-2-carboxylic acid 453.44 benzyl ester 164 (±)-1-(2-Carboxymethoxy-5- C25H21 0.94 486.0 chloro-phenyl)-3,4-dihydro-1H- NO5Cl2 LC-MS 1FA isoquinoline-2-carboxylic acid 2- 486.35 chloro-benzyl ester 165 (±)-1-(2-Carboxymethoxy-5-fluoro- C25H21 0.91 470.1 phenyl)-3,4-dihydro-1H- NO5ClF LC-MS 1FA isoquinoline-2-carboxylic acid 2- 469.90 chloro-benzyl ester 166 (±)-1-(2-Carboxymethoxy-5-fluoro- C23H26 0.91 416.2 phenyl)-3,4-dihydro-1H- NO5F LC-MS 1FA isoquinoline-2-carboxylic acid 2,2- 415.46 dimethyl-propyl ester 167 (±)-1-(2-Carboxymethoxy-5-fluoro- C22H24 0.88 402.2 phenyl)-3,4-dihydro-1H- NO5F LC-MS 1FA isoquinoline-2-carboxylic acid 401.43 butyl ester 168 (±)-1-(2-Carboxymethoxy-5-fluoro- C25H22 0.85 452.1 phenyl)-3,4-dihydro-1H- NO6F LC-MS 1FA isoquinoline-2-carboxylic acid 2- 451.45 methoxy-phenyl ester 169 (±)-1-(2-Carboxymethoxy-5-fluoro- C24H20 0.85 422.1 phenyl)-3,4-dihydro-1H- NO5F LC-MS 1FA isoquinoline-2-carboxylic acid 421.42 phenyl ester 170 (±)-1-(2-Carboxymethoxy-5-fluoro- C24H19 0.88 456.1 phenyl)-3,4-dihydro-1H- NO5ClF LC-MS 1FA isoquinoline-2-carboxylic acid 2- 455.87 chloro-phenyl ester 171 (±)-1-(2-Carboxymethoxy-5-fluoro- C22H24 0.88 402.2 phenyl)-3,4-dihydro-1H- NO5F LC-MS 1FA isoquinoline-2-carboxylic acid 401.43 isobutyl ester 172 (±)-1-(2-Carboxymethoxy-5-fluoro- C21H22 0.76 404.0 phenyl)-3,4-dihydro-1H- NO6F LC-MS 2 isoquinoline-2-carboxylic acid 2- 403.41 methoxy-ethyl ester 173 (±)-1-(2-Carboxymethoxy-5-fluoro- C25H22 0.85 452.1 phenyl)-3,4-dihydro-1H- NO6F LC-MS 1FA isoquinoline-2-carboxylic acid 4- 451.45 methoxy-phenyl ester 174 (S)-1-(2-Carboxymethoxy-5- C25H21 0.94 486.1 chloro-phenyl)-3,4-dihydro-1H- NO5Cl2 LC-MS 1FA isoquinoline-2-carboxylic acid 2- 486.35 chloro-benzyl ester 175 (±)-1-(2-Carboxymethoxy-5- C25H20 0.96 504.0 chloro-phenyl)-5-fluoro-3,4- NO5Cl2F LC-MS 1FA dihydro-1H-isoquinoline-2- 504.34 carboxylic acid 2-chloro-benzyl ester

Method B: To a solution of triphosgene (22 mg, 0.07 mmol, 0.33 eq.) in MeCN (0.15 mL) at −10° C. (acetone/ice bath), a solution of an alcohol (0.25 mmol, 1.10 eq.) and NEt₃ (41 μL, 0.31 mmol, 1.4 eq.) in MeCN (0.8 mL) was added over a period of 15 min. The mixture was stirred for an additional 30 min at −10° C. and then a solution of (±)-[4-fluoro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (77 mg, 0.22 mmol, 1.00 eq.) and NEt₃ (87 μL, 0.62 mmol, 2.8 eq.) in MeCN (0.46 mL) was slowly added. The reaction mixture was slowly warmed to r.t. (ice bath during 30 min, then r.t.) and stirred at r.t. for 18 hours. The reaction mixture was diluted with AcOEt, washed with water and sat. aq. NaCl, dried over MgSO₄, filtered and evaporated. To a solution of the residue in DMF (0.5 mL), 1M aq. NaOH soln. (0.5 mL) was added. The solution was stirred at r.t. for 18 hours. The reaction mixture was neutralized with formic acid, then purified by prep. HPLC (column: Atlantis, 30×75 mm, 5 um, UV/MS, acidic conditions) to give the desired acid as a white solid.

Listed in Table 9 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding amine of Structure 2 and the corresponding alcohol as starting materials.

TABLE 9 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 176 (±)-1-(2-Carboxymethoxy-5- C26H23 0.97 500.1 chloro-phenyl)-3,4-dihydro-1H- NO5Cl2 LC-MS 1FA isoquinoline-2-carboxylic acid 2- 500.38 (2-chloro-phenyl)-ethyl ester 177 (±)-1-(2-Carboxymethoxy-5-fluoro- C26H23 0.94 484.1 phenyl)-3,4-dihydro-1H- NO5ClF LC-MS 1FA isoquinoline-2-carboxylic acid 2- 483.92 (2-chloro-phenyl)-ethyl ester 178 (±)-1-(2-Carboxymethoxy-5-fluoro- C24H19 0.90 456.1 phenyl)-3,4-dihydro-1H- NO5ClF LC-MS 1FA isoquinoline-2-carboxylic acid 3- 455.87 chloro-phenyl ester 179 (±)-1-(2-Carboxymethoxy-5- C26H22 0.98 518.0 chloro-phenyl)-5-fluoro-3,4- NO5Cl2F LC-MS 1FA dihydro-1H-isoquinoline-2- 518.37 carboxylic acid 2-(2-chloro- phenyl)-ethyl ester

Example 180 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C27H26NO5C1, MW=479.96)

Trifluoroacetic acid (0.92 mL, 11.8 mmol, 20.0 eq.) was added to a solution of (±)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (280 mg, 0.59 mmol, 1.0 eq.) in DCM (1 mL). The resulting mixture was stirred at r.t. during 5 hours. The mixture was concentrated in vacuo. To an-ice cooled suspension of the residue and triethylamine (0.41 mL, 2.95 mmol, 5.0 eq.) in DCM (1 mL), benzyl chloroformate (0.18 mL, 1.18 mmol, 2.0 eq.) was added dropwise. Upon completion of the addition, the cooling bath was removed and the suspension was stirred at r.t. for 18 hours. The reaction was quenched with 1M aq. citric acid soln. (5 mL). The layers were separated. The aq. phase was extracted with DCM (3×2 mL). The comb. org. phases were dried over MgSO₄ and concentrated in vacuo. The residue was dissolved in DMF (1 mL), 1M aq. NaOH soln. (1 mL) was added. The resulting solution was stirred at r.t. for 18 hours. The solution was neutralized with formic acid (1 mL), filtered, and then purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid.

LC-MS 1 FA: t_(R)=0.98 min; [M+H]⁺=480.1

Copper Mediated Sulfonylation and Subsequent Saponification

A mixture of (±)-7-bromo-1-(2-ethoxycarbonylmethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (54 mg, 0.10 mmol, 1.0 eq.), a sodium sulfinate (0.10 mmol, 1.0 eq.), L-proline (2.3 mg, 0.02 mmol, 0.2 eq.), 1M NaOH (20 μL, 0.02 mmol, 0.2 eq.), and copper (I) iodide (1.9 mg, 0.01 mmol, 0.1 eq.) in DMSO (1 mL) was stirred at 100° C. for 48 hours. The mixture was allowed to cool to r.t. and partitioned between AcOEt (15 mL), and H₂O (15 mL). The layers were separated and the aq. phase was extracted with AcOEt (2×15 mL). The comb. org. phases were dried over MgSO₄ and concentrated in vacuo. The residue was dissolved in THF (0.5 mL), 1M aq. NaOH (0.28 mL) was added and the mixture was stirred at r.t. for 14 hours. The org. solvent was removed in vacuo. The residue was diluted with water (2 mL) and acidified with 1M aq. HCl soln. The mixture was extracted with DCM (3×5 mL). The comb. org. phases were concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters Atlantis, 19×50 mm, 10 um, UV/MS, acidic conditions) to give the desired acid as a white solid.

Listed in Table 10 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with (±)-7-bromo-1-(2-ethoxycarbonylmethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester, (±)-5-bromo-1-(2-ethoxycarbonylmethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester, or (±)-1-(5-bromo-2-ethoxycarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester and the corresponding sodium sulfinate as starting materials.

TABLE 10 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 181 (±)-1-(2-Carboxymethoxy-5-fluoro- C27H26 0.78 528.1 phenyl)-7-ethanesulfonyl-3,4- NO7FS LC-MS 1FA dihydro-1H-isoquinoline-2- 527.57 carboxylic acid benzyl ester 182 (±)-1-(2-Carboxymethoxy-5- C26H25 0.74 496.1 methanesulfonyl-phenyl)-3,4- NO7S LC-MS 1FA dihydro-1H-isoquinoline-2- 495.55 carboxylic acid benzyl ester 183 (±)-1-(5-Benzenesulfonyl-2- C31H27 0.84 558.1 carboxymethoxy-phenyl)-3,4- NO7S LC-MS 1FA dihydro-1H-isoquinoline-2- 557.62 carboxylic acid benzyl ester 184 (±)-1-(2-Carboxymethoxy-5- C27H27 0.77 510.1 ethanesulfonyl-phenyl)-3,4- NO7S LC-MS 1FA dihydro-1H-isoquinoline-2- 509.58 carboxylic acid benzyl ester 185 (±)-1-(2-Carboxymethoxy-5-fluoro- C26H24 0.75 514.1 phenyl)-5-methanesulfonyl-3,4- NO7FS LC-MS 1FA dihydro-1H-isoquinoline-2- 513.54 carboxylic acid benzyl ester 186 (±)-1-(2-Carboxymethoxy-5-fluoro- C27H26 0.78 528.1 phenyl)-5-ethanesulfonyl-3,4- NO7FS LC-MS 1FA dihydro-1H-isoquinoline-2- 527.57 carboxylic acid benzyl ester 187 (±)-5-Benzenesulfonyl-1-(2- C31H26 0.85 576.1 carboxymethoxy-5-fluoro-phenyl)- NO7FS LC-MS 1FA 3,4-dihydro-1H-isoquinoline-2- 575.61 carboxylic acid benzyl ester

Suzuki Cross-Coupling and Subsequent Saponification

To a mixture under N₂ of (±)-1-(5-bromo-2-ethoxycarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (52 mg, 0.10 mmol, 1.00 eq.), a boronic acid (0.10 mmol, 1.0 eq.), and sodium carbonate (42 mg, 0.40 mmol, 4.00 eq.) in toluene/EtOH/water 20:4:1 (2.5 mL), tetrakis(triphenylphosphine) palladium (0) (6 mg, 0.005 mmol, 0.05 eq.) was added. The mixture was stirred at 100° C. for 24 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was partitioned between AcOEt (10 mL) and water (10 mL). The layers were separated. The org. phase was washed with sat. aq. NaCl soln. (1×5 mL), dried over MgSO₄, and filtered through Celite. The filtrate was concentrated in vacuo. The residue was dissolved in THF (0.5 mL). 1M aq. NaOH (0.28 mL) was added and the mixture was stirred at r.t. for 14 hours. The org. solvent was removed in vacuo. The residue was diluted with water (2 mL) and acidified with 1M aq. HCl soln. The mixture was extracted with DCM (3×5 mL). The comb. org. phases were concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters Atlantis, 19×50 mm, 10 um, UV/MS, acidic conditions) to give the desired acid as a white solid.

Listed in Table 11 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding boronic acid as starting material.

TABLE 11 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 188 (±)-1-(2-Carboxymethoxy-5- C29H25 0.76 496.2 pyrimidin-5-yl-phenyl)-3,4-dihydro- N3O5 LC-MS 1FA 1H-isoquinoline-2-carboxylic acid 495.53 benzyl ester 189 (±)-1-(4-Carboxymethoxy-4′- C31H26 0.96 512.2 fluoro-biphenyl-3-yl)-3,4-dihydro- NO5F LC-MS 1FA 1H-isoquinoline-2-carboxylic acid 511.55 benzyl ester

Alcohol Alkylation and Subsequent Saponification

Method A: To an ice-cooled solution of an alcohol (0.42 mmol, 5.0 eq.) in DMF (0.6 mL), sodium hydride (25 mg, 0.62 mmol, 7.0 eq.) was added. The mixture was stirred at 0° C. for 1 hour. A solution of (±)-{2-[2-(2-bromo-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic acid ethyl ester (40 mg, 0.09 mmol, 1.0 eq.) in DMF (0.6 mL) was added and the reaction mixture was stirred at r.t. for 18 hours. Water (20 μL) was added and the mixture was further stirred at r.t. during 1 hour. The reaction mixture was concentrated in vacuo. The residue was dissolved in THF (0.7 mL). 1M aq. NaOH soln. (0.3 mL) was added. The solution was stirred at r.t. for 18 hours. The reaction mixture was acidified with 1M aq. HCl soln. (0.5 mL) and concentrated in vacuo. The residue, redissolved in DMF (1.2 mL), was purified by prep. HPLC (column: Atlantis, 19×50 mm, 5 um, UV/MS, acidic conditions) to give the desired acid.

Listed in Table 12 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding alcohol as starting material.

TABLE 12 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 190 (±)-(2-{2-[2-(3-Chloro-benzyloxy)- C26H23 0.86 484.1 acetyl]-1,2,3,4-tetrahydro- NO5ClF LC-MS 1FA isoquinolin-1-yl}-4-fluoro- 483.92 phenoxy)-acetic acid 191 (±)-(2-{2-[2-(4-Chloro-benzyloxy)- C26H23 0.86 484.1 acetyl]-1,2,3,4-tetrahydro- NO5ClF LC-MS 1FA isoquinolin-1-yl}-4-fluoro- 483.92 phenoxy)-acetic acid 192 (±)-(4-Fluoro-2-{2-[2-(2-methyl- C27H26 0.85 464.2 benzyloxy)-acetyl]-1,2,3,4- NO5F LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 463.50 phenoxy)-acetic acid 193 (±)-(4-Fluoro-2-{2-[2-(3-methyl- C27H26 0.85 464.2 benzyloxy)-acetyl]-1,2,3,4- NO5F LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 463.50 phenoxy)-acetic acid 194 (±)-(4-Fluoro-2-{2-[2-(4-methyl- C27H26 0.85 464.1 benzyloxy)-acetyl]-1,2,3,4- NO5F LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 463.50 phenoxy)-acetic acid 195 (±)-(4-Fluoro-2-{2-[2-(3-methoxy- C27H26 0.81 480.2 benzyloxy)-acetyl]-1,2,3,4- NO6F LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 479.50 phenoxy)-acetic acid 196 (±)-(4-Fluoro-2-{2-[2-(4-methoxy- C27H26 0.80 480.1 benzyloxy)-acetyl]-1,2,3,4- NO6F LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 479.50 phenoxy)-acetic acid

Method B: To a solution of (±)-{2-[2-(2-bromo-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic acid ethyl ester (50 mg, 0.11 mmol, 1.0 eq.) and an alcohol (0.13 mmol, 1.2 eq.) in toluene (1 mL), 30% aq. NaOH (1 mL) and tetrabutyl ammonium hydrogen sulfate (7.3 mg, 0.02 mmol, 0.2 eq.) were added. After 18 hours of vigorous stirring at r.t., the reaction mixture was diluted with water (2 mL), acidified with 1M aq. HCl and extracted with DCM (3×). The comb. org. layers were dried over MgSO₄, filtered and concentrated in vacuo. The crude mixture, redissolved in DMF (1.2 mL), was purified by prep. HPLC (column: Atlantis, 19×50 mm, 5 um, UV/MS, acidic conditions) to give the desired acid.

Listed in Table 13 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding alcohol as starting material.

TABLE 13 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 197 (±)-(4-Fluoro-2-{2-[2-(1-methyl-1H- C24H24 0.68 454.2 pyrazol-3-ylmethoxy)-acetyl]- N3O5F LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 453.47 yl}-phenoxy)-acetic acid 198 (±)-(4-Fluoro-2-{2-[2-(2-methoxy- C27H26 0.82 480.2 benzyloxy)-acetyl]-1,2,3,4- NO6F LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 479.50 phenoxy)-acetic acid

Urea Synthesis and Subsequent Saponification

Method A: An isocyanate (0.22 mmol, 1.1 eq.) was added dropwise to an ice-cooled solution of (±)-[4-fluoro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (73 mg, 0.20 mmol, 1.0 eq.) and NEt₃ (0.09 mL, 0.62 mmol, 3.1 eq.) in DCM (5.5 mL). The resulting reaction mixture was stirred at r.t. for 60 hours. The mixture was diluted with DCM and washed with sat. aq. NaHCO₃ soln. and water. The organic layer was dried over MgSO₄, filtered and concentrated in vacuo. To a solution of the crude product in DMF (0.9 mL), 1M aq. NaOH soln. (0.25 mL) was added. The solution was stirred at r.t. for 18 hours. The solution was acidified with 1M aq. HCl (0.25 mL), filtered, and purified by prep. HPLC (column: Waters X-Bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) to give the desired acid.

Listed in Table 14 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding amine of Structure 2 and the corresponding isocyanate as starting materials.

TABLE 14 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 199 (±)-[2-(2-Benzylcarbamoyl-1,2,3,4- C25H23 0.79 435.2 tetrahydro-isoquinolin-1-yl)-4- N2O4F LC-MS 1FA fluoro-phenoxy]-acetic acid 434.47 200 (±)-[4-Fluoro-2-(2- C26H25 0.82 449.2 phenethylcarbamoyl-1,2,3,4- N2O4F LC-MS 1FA tetrahydro-isoquinolin-1-yl)- 448.49 phenoxy]-acetic acid 201 (±)-{4-Fluoro-2-[2-(2-methoxy- C26H25 0.79 465.2 benzylcarbamoyl)-1,2,3,4- N2O5F LC-MS 1FA tetrahydro-isoquinolin-1-yl]- 464.49 phenoxy}-acetic acid 202 (±)-{4-Chloro-2-[2-(2-methoxy- C26H25 0.83 481.1 benzylcarbamoyl)-1,2,3,4- N2O5Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl]- 480.95 phenoxy}-acetic acid 203 (±)-{2-[2-(2-Chloro- C25H22 0.82 469.1 benzylcarbamoyl)-1,2,3,4- N2O4ClF LC-MS 1FA tetrahydro-isoquinolin-1-yl]-4- 468.91 fluoro-phenoxy}-acetic acid

Method B: Example 204: (±)-(2-{2-[2-(2-Chloro-phenyl)-ethylcarbamoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic acid (C26H24N2O4CIF, MW=482.94)

To a solution of triphosgene (20 mg, 0.07 mmol, 0.33 eq.) in MeCN (0.3 mL) at −10° C. (acetone/ice bath), a solution of 2-(2-chlorophenyl)ethylamine (33 μL, 0.22 mmol, 1.10 eq.) and triethylamine (39 μL, 0.28 mmol, 1.30 eq.) in MeCN (2 mL) was added over a period of 15 min. The mixture was stirred for an additional 30 min at 0° C. and then a solution of (±)-[4-fluoro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (73 mg, 0.20 mmol, 1.00 eq.) and triethylamine (78 μL, 0.56 mmol, 2.80 eq.) in MeCN (1 mL) was slowly added. The reaction mixture was slowly warmed to r.t. (ice bath during 30 min, then r.t.) and stirred at r.t. for 60 hours. The mixture was diluted with AcOEt, washed with water and sat. aq. NaCl soln., dried over MgSO₄, filtered, and evaporated. To a solution of the crude product in DMF (0.9 mL), 1M aq. NaOH soln. (0.25 mL) was added. The solution was stirred at r.t. for 18 hours. The solution was acidified with 1M aq. HCl soln. (0.25 mL) then purified by prep. HPLC (column: Waters X-Bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) to afford the title compound.

LC-MS 1 FA: t_(R)=0.84 min; [M+H]⁺=483.1

Sulfonamide Formation and Subsequent Saponification

A sulfonyl chloride (0.18 mmol, 1.0 eq.) and DIPEA (0.33 mL, 1.92 mmol, 10.6 eq.) were added to a solution of (±)-{2-[2-(2-amino-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic acid ethyl ester hydrochloride (81 mg, 0.18 mmol, 1.0 eq.) in DCM (3 mL). The mixture was stirred at r.t. for 2 hours. 1M aq. KH₂PO₄ soln. (3 mL) was added to the mixture. The layers were separated and the aq. phase was extracted with DCM (2×). The comb. org. phases were concentrated in vacuo. The residue was dissolved in THF (0.8 mL) and 1M aq. NaOH soln. (0.4 mL) was added. The solution was stirred at r.t. for 18 hours. The solution was diluted with water (2 mL) and 1M aq. HCl soln. (0.4 mL) followed by DCM. The mixture was shaked then the layers were separated and the aq. phase was extracted with DCM (2×). The comb. org. phases were concentrated in vacuo. The crude mixture, redissolved in DMF (1.2 mL), was purified by prep. HPLC (column: Atlantis, 19×50 mm, 5 um, UV/MS, acidic conditions) to give the desired acid.

Listed in Table 15 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding sulfonyl chloride as starting material.

TABLE 15 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 205 (±)-{2-[2-(2- C25H23 0.75 499.1 Benzenesulfonylamino-acetyl)- N2O6FS LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 498.53 yl]-4-fluoro-phenoxy}-acetic acid 206 (±)-(2-{2-[2-(3,5-Dimethyl- C24H24 0.75 518.1 isoxazole-4-sulfonylamino)- N3O7FS LC-MS 1FA acetyl]-1,2,3,4-tetrahydro- 517.53 isoquinolin-1-yl}-4-fluoro- phenoxy)-acetic acid 207 (±)-(4-Fluoro-2-{2-[2-(3-fluoro- C25H22 0.77 517.1 benzenesulfonylamino)-acetyl]- N2O6F2S LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 516.52 yl}-phenoxy)-acetic acid 208 (±)-(4-Fluoro-2-{2-[2-(2-fluoro- C25H22 0.76 517.1 benzenesulfonylamino)-acetyl]- N2O6F2S LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 516.52 yl}-phenoxy)-acetic acid 209 (±)-(2-{2-[2-(3,4-Difluoro- C25H21 0.79 535.1 benzenesulfonylamino)-acetyl]- N2O6F3S LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 534.51 yl}-4-fluoro-phenoxy)-acetic acid

Sulfonamide Formation, Alkylation, and Subsequent Saponification

A sulfonyl chloride (0.18 mmol, 1.0 eq.) and DIPEA (0.33 mL, 1.92 mmol, 10.6 eq.) were added to a solution of (±)-{2-[2-(2-amino-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic acid ethyl ester hydrochloride (81 mg, 0.18 mmol, 1.0 eq.) in DCM (3 mL). The mixture was stirred at r.t. for 2 hours. 1M aq. KH₂PO₄ soln. (3 mL) was added to the mixture. The layers were separated and the aq. phase was extracted with DCM (2×). The comb. org. phases were concentrated in vacuo. To an ice-cooled solution of the residue in DMF (1 mL), sodium hydride (9 mg, 0.22 mmol, 1.2 eq.) was added. The reaction mixture was stirred at r.t. for 30 min. Methyl iodide (23 μl, 0.36 mmol, 2.0 eq.) was added and the resulting mixture was stirred at r.t. for 18 hours. The mixture was poured in H₂O and extracted with DCM (3×). The comb. org. phases were concentrated in vacuo. The residue was dissolved in DMF (0.8 mL) and 1M aq. NaOH soln. (0.4 mL) was added. The solution was stirred at r.t. for 18 hours. The solution was diluted with water (2 mL) and 1M aq. HCl soln. (0.4 mL) followed by DCM. The mixture was shaked then the layers were separated and the aq. phase was extracted with DCM (2×). The comb. org. phases were concentrated in vacuo. The crude mixture, redissolved in DMF (1.2 mL), was purified by prep. HPLC (column: Atlantis, 19×50 mm, 5 um, UV/MS, acidic conditions) to give the desired acid.

Listed in Table 16 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding sulfonyl chloride as starting material.

TABLE 16 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 210 (±)-(2-{2-[2-(N-Benzenesulfonyl-N- C26H25 0.79 513.1 methyl-amino)-acetyl]-1,2,3,4- N2O6FS LC-MS 1FA tetrahydro-isoquinolin-1-yl}-4- 512.56 fluoro-phenoxy)-acetic acid 211 (±)-[4-Fluoro-2-(2-{2-[N-(3-fluoro- C26H24 0.80 531.1 benzenesulfonyl)-N-methyl- N2O6F2S LC-MS 1FA amino]-acetyl}-1,2,3,4-tetrahydro- 530.55 isoquinolin-1-yl)-phenoxy]-acetic acid 212 (±)-[2-(2-{2-[N-(3,4-Difluoro- C26H23 0.82 549.1 benzenesulfonyl)-N-methyl- N2O6F3S LC-MS 1FA amino]-acetyl}-1,2,3,4-tetrahydro- 548.54 isoquinolin-1-yl)-4-fluoro- phenoxy]-acetic acid

Example 213 (±)-1-(5-Carbamoyl-2-carboxymethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C26H24N2O6, MW=460.49)

To a solution of (±)-1-(5-cyano-2-ethoxycarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (141 mg, 0.30 mmol, 1.0 eq.) in EtOH (0.5 mL) and water (0.12 mL), hydrido(dimethylphosphinous acid-kP)[hydrogen bis(dimethylphosphinito-kP)]platinum(II) (26 mg, 0.06 mmol, 0.2 eq.) was added in one portion at r.t. The reaction mixture was stirred at 70° C. for 1 hour, then allow to cool to r.t. The product solution was then filtered through a short column containing a layer of Na₂SO₄ on top of a layer of SiO₂ (each 1 cm deep), eluting with AcOEt (200 mL). The filtrate was concentrated in vacuo. To a solution of the residue in DMF (2 mL), 1M aq. NaOH (0.5 ml) was added. The resulting solution was stirred at r.t. for 6 hours. The mixture was neutralized with formic acid (0.5 mL), filtered, and purified by prep. HPLC (column: Waters X-Bridge, 19×50 mm, 5 um, UV/MS, acidic conditions) to give the desired acid as a white solid.

LC-MS 1 FA: t_(R)=0.67 min; [M+H]⁺=461.2

Example 214 (±)-1-[2-Carboxymethoxy-5-(5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C27H23N3O6S, MW=517.56)

A mixture of hydroxylamine hydrochloride (139 mg, 2.00 mmol, 10.0 eq.) and NaHCO₃ (202 mg, 2.40 mmol, 12.0 eq.) in DMSO (1 mL) was stirred at 50° C. for 1 hour. (±)-1-(5-Cyano-2-ethoxycarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (94 mg, 0.20 mmol, 1.0 eq.) was added and the resulting new mixture was stirred at 80° C. for 1 hour. Water was added to the reaction mixture followed by AcOEt. The layers were separated and the org. phase was washed with sat. aq. NaCl, dried over MgSO₄, filtered and concentrated in vacuo. The residue was dissolved in THF (1 mL). 1,1′-thiocarbonyldiimidazole (39 mg, 0.21 mmol, 1.05 eq) and DBU (21 μL, 0.14 mmol, 0.7 eq.) were added and the mixture was stirred at r.t. for 3 hours. Water was added and the mixture was extracted with AcOEt. The layers were separated and the org. phase was successively washed with sat. aq. NaHCO₃ soln. and sat. aq. NaCl soln. then dried over MgSO₄, filtered and concentrated in vacuo. To a solution of the residue in THF (0.9 mL), 1M aq. NaOH soln. (0.25 mL) was added. The solution was stirred at r.t. for 18 hours.

The solution was diluted with water (2 mL) and 1M aq. HCl soln. (0.25 mL) followed by DCM. The mixture was shaked then the layers were separated and the aq. phase was extracted with DCM (2×). The comb. org. phases were concentrated in vacuo. The crude mixture, redissolved in DMF (1.2 mL), was purified by prep. HPLC (column: Atlantis, 19×50 mm, 5 um, UV/MS, acidic conditions) to give the desired acid.

LC-MS 1FA: t_(R)=0.79 min; [M+H]⁺=518.1

Example 215 (±)-1-(2-Carboxymethoxy-4-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C25H22NO5F, MW=435.45)

A mixture under N₂ of (±)-1-(2-allyloxy-4-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (200 mg, 0.48 mmol, 1.00 eq.), 1,3-dimethylbarbituric acid (150 mg, 0.96 mmol, 2.00 eq.) and tetrakis(triphenylphosphine) palladium (0) (28 mg, 0.02 mmol, 0.05 eq.) in MeOH (5 mL) was stirred at r.t. for 5 hours. The mixture was partitioned between AcOEt (25 mL) and water (25 mL). The layers were separated and the aq. phase was extracted with AcOEt (2×25 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×25 mL), dried over MgSO₄, and concentrated in vacuo. To a solution of the residue and Cs₂CO₃ (468 mg, 1.44 mmol, 3.00 eq.) in DMF (3 mL), ethyl bromoacetate (79 μL, 0.72 mmol, 1.50 eq.) was added. The reaction mixture was stirred at 50° C. for 5 hours. The reaction mixture was diluted with water (25 mL) and AcOEt (50 mL). The layers were separated. The aq. phase was extracted with AcOEt (2×25 mL). The comb. org. phases were washed with water (1×25 mL), sat. aq. NaCl soln. (1×25 mL), dried over MgSO₄, and concentrated in vacuo. To a solution of the residue in DMF (2 mL), 1M aq. NaOH (2 mL) was added. The resulting solution was stirred at 50° C. for 5 hours. The solution was neutralized with formic acid (1 mL) and then purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid.

LC-MS 1 FA: t_(R)=0.87 min; [M+H]⁺=436.1

Example 216 (±)-1-(2-Carboxymethoxy-6-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C25H22NO5F, MW=435.45)

A mixture under N₂ of (±)-1-(2-allyloxy-6-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (60 mg, 0.14 mmol, 1.00 eq.), 1,3-dimethylbarbituric acid (45 mg, 0.29 mmol, 2.00 eq.) and tetrakis(triphenylphosphine) palladium (0) (8 mg, 7 μmol, 0.05 eq.) in MeOH (5 mL) was stirred at 50° C. for 5 hours. The mixture was partitioned between AcOEt (25 mL) and water (25 mL). The layers were separated and the aq. phase was extracted with AcOEt (2×25 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×25 mL), dried over MgSO₄, and concentrated in vacuo. To a solution of the residue and Cs₂CO₃ (140 mg, 0.43 mmol, 3.00 eq.) in DMF (2 mL), ethyl bromoacetate (24 μL, 0.22 mmol, 1.50 eq.) was added. The reaction mixture was stirred at 50° C. for 5 hours. The reaction mixture was diluted with water (25 mL) and AcOEt (50 mL). The layers were separated. The aq. phase was extracted with AcOEt (2×25 mL). The comb. org. phases were washed with water (1×25 mL), sat. aq. NaCl soln. (1×25 mL), dried over MgSO₄, and concentrated in vacuo. To a solution of the residue in DMF (2 mL), 1M aq. NaOH (2 mL) was added. The resulting solution was stirred at 50° C. for 5 hours. The solution was neutralized with formic acid (1 mL) and then purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid.

LC-MS 1 FA: t_(R)=0.86 min; [M+H]⁺=436.2

Example 217 (±)-1-[2-(3-Carboxy-propoxy)-5-fluoro-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C27H26NO5F, MW=463.50)

Ethyl-4-bromobutyrate (45 μL, 0.30 mmol, 1.50 eq.) was added to a solution of (±)-1-(5-fluoro-2-hydroxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (75 mg, 0.20 mmol, 1.00 eq.) and K₂CO₃ (83 mg, 0.60 mmol) in DMF (0.7 mL). The mixture was stirred at r.t. for 2 hours. Ethyl-4-bromobutyrate (22 μL, 0.15 mmol, 0.75 eq.) was added again and the mixture was stirred at r.t. for 18 hours. The reaction mixture was diluted with AcOEt and water. The layers were separated and the aq. phase was extracted with AcOEt (2×). The combined org. phases were washed with water and sat. aq. NaCl soln., dried over MgSO₄, filtered and concentrated in vacuo. To a solution of the crude ester in THF (0.9 mL), 1M aq. NaOH soln. (0.50 mL) was added. The resulting solution was stirred at r.t. during 62 hours. The org. solvent was removed in vacuo. The residue was diluted with water and 1M aq. HCl soln. (0.8 mL) followed by DCM. The mixture was shaked then the layers were separated and the aq. phase was extracted with DCM (2×). The comb. org. phases were dried over MgSO₄, filtered and concentrated in vacuo. The crude mixture, redissolved in DMF (1.2 mL), was purified by prep. HPLC (column: Atlantis, 19×50 mm, 5 um, UV/MS, acidic conditions) and evaporated (genevac) to give the desired acid.

LC-MS 1 FA: t_(R)=0.89 min; [M+H]⁺=464.2

Example 218 (±)-{4-Cyano-2-[2-(trans-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid (C28H24N2O4, MW=452.51)

To a solution of (±)-1-(5-cyano-2-ethoxycarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (188 mg, 0.40 mmol, 1.0 eq.) in DCM (1 mL), a solution of 2-bromo-1,3,2-benzodioxaborole (159 mg, 0.80 mmol, 2.0 eq.) in DCM (2 mL) was added dropwise. The mixture was stirred at r.t. for 2 hours. Water (2 mL) was added. The mixture was stirred at r.t. for 20 min, then diluted with DCM (30 mL). The mixture was washed with 10% aq. NaOH soln. (2×15 mL), with sat. aq. NaCl soln. (1×15 mL), and dried over MgSO₄. The dried org. layer was treated with 4M HCl in dioxane (4 mL), stirred at r.t. for 1 hour, and concentrated in vacuo. The residue was triturated with heptane and filtered to give the HCl salt as a white solid. To a mixture of the resulting salt and trans-2-phenylcyclopropane-1-carboxylic acid (65 mg, 0.40 mmol, 1.0 eq.) in DMF (2 mL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimid hydrochlorid (115 mg, 0.60 mmol, 1.5 eq.) and 4-(dimethylamino)pyridine (147 mg, 1.20 mmol, 3.0 eq.) were added in sequence. The mixture was stirred at r.t. for 20 hours. The mixture was diluted with AcOEt (15 mL). The diluted solution was washed with 1M aq. HCl soln. (2×5 mL), sat. aq. NaHCO₃ soln. (2×5 mL), sat. aq. NaCl soln. (1×5 mL), dried over MgSO₄, and concentrated in vacuo. The residue was dissolved in THF (1 mL). 1M aq. NaOH (0.56 mL) was added. The mixture was stirred at r.t. for 18 hours. The mixture was concentrated in vacuo. The residue was diluted with water (2 mL) and acidified with 1M aq. HCl soln. The mixture was extracted with DCM/THF 2:1 (3×6 mL). The comb. org. phases were concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters X-bridge, 19×50 mm, 10 um, UV/MS, acidic conditions) to give the desired acid as a white foam.

LC-MS 1 FA: t_(R)=0.79 min; [M+H]⁺=453.2

Example 219 (±)-1-(2-Carboxymethoxy-5-cyano-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C26H22N2O5, MW=442.47)

To a solution of (±)-1-(5-bromo-2-ethoxycarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (105 mg, 0.20 mmol, 1.0 eq.) in DMF (10 mL) were added zinc cyanide (23 mg, 0.20 mmol, 1.0 eq.) and tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol, 0.1 eq.). The resulting suspension was stirred at 110° C. for 18 hours. After cooling, Et₂O (100 mL) was added and the solution was washed with sat. aq. NaCl soln. (2×120 mL). The organic layer was dried over MgSO₄, filtered, and the solvent was removed under vacuum. To a solution of the crude product in DMF (0.9 mL) 1M aq. NaOH soln. (0.25 mL) was added. The solution was stirred at r.t. for 18 hours. The solution was acidified with 1M aq. HCl soln.

(0.25 mL) then purified by prep. HPLC (column: Waters X-Bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) to give the desired acid.

LC-MS 1 FA: t_(R)=0.81 min; [M+H]⁺=443.1

Example 220 1-[2-((R)-1-Carboxy-ethoxy)-5-chloro-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C26H24NO5C1, MW=465.93)

To a solution of (±)-1-(5-chloro-2-hydroxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (192 mg, 0.30 mmol, 1.0 eq.) in MeCN (1 mL), (S)-2-(toluene-4-sulfonyloxy)-propionic acid methyl ester (80 mg, 0.30 mmol, 1.0 eq.) and potassium carbonate anhydrous (83 mg, 0.60 mmol, 2.0 eq.) were added and the mixture was heated to 65° C. for 18 hours. (S)-2-(Toluene-4-sulfonyloxy)-propionic acid methyl ester (40 mg, 0.15 mmol, 0.5 eq.) was added again and the mixture was heated at 90° C. for 4 hours. The mixture was allowed to cool to r.t. and extracted with Et₂O (2×), dried over MgSO₄, filtered, and concentrated in vacuo. To a solution of the crude ester in THF (1.3 mL), 1M aq. NaOH soln. (0.38 mL) was added. The solution was stirred at r.t. for 18 hours. The solution was diluted with water (2 mL) and 1M aq. HCl soln. (0.38 mL) followed by DCM. The mixture was shaked then the layers were separated and the aq. phase was extracted with DCM (2×). The comb. org. phases were concentrated in vacuo. The crude mixture, redissolved in DMF (1.2 mL), was purified by prep. HPLC (column: Atlantis, 19×50 mm, 5 um, UV/MS, acidic conditions) to give the desired acid.

LC-MS 1 FA: t_(R)=0.93 min; [M+H]⁺=466.1

Example 221 (S)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C25H22NO5F, MW=435.45)

(±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester was separated by chiral prep. HPLC (column: ChiralPak AD-H, 20×250 mm, 5 μm, UV, eluent: Hept/EtOH+0.1% TFA 70/30) to yield 30.5 mg of the (R)-enantiomer and 26.1 mg of the (S)-enantiomer. Due the presence of EtOH in the eluent mixture, the acids were partially esterified. To a solution of the (S)-enantiomer in THF (0.6 mL), 1M aq. NaOH soln. (0.18 mL) was added. The solution was stirred at r.t. during 2 hours. The org. solvent was removed in vacuo. The residue was diluted with water and 1M aq. HCl soln. (0.18 mL) followed by DCM. The mixture was shaked then the layers were separated and the aq. phase was extracted with DCM (2×). The comb. org. phases were concentrated in vacuo. The residue, redissolved in DMF (1.2 mL) was purified by prep. HPLC (column: Waters X-Bridge, 19×50 mm, 5 um, UV/MS, acidic conditions) to give the desired acid

LC-MS 1 FA: t_(R)=0.87 min; [M+H]⁺=436.1

Example 222 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-5-methanesulfonylamino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C26H25N2O7FS, MW=528.56)

A mixture under Ar of (±)-5-bromo-1-(2-ethoxycarbonylmethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (108 mg, 0.20 mmol, 1.00 eq.), methanesulfonamide (23 mg, 0.24 mmol, 1.20 eq.), N,N-dimethylglycine (4.3 mg, 0.04 mmol, 0.2 eq.), potassium phosphate tribasic (106 mg, 0.50 mmol, 2.5 eq.), and copper (I) iodide (7.6 mg, 0.04 mmol, 0.2 eq.) in DMF (2 mL) was stirred at 150° C. for 48 hours. The mixture was allowed to cool to r.t. and partitioned between AcOEt (25 mL) and H₂O (25 mL). The layers were separated and the aq. phase was extracted with AcOEt (2×25 mL). The comb. org. phases were dried over MgSO₄ and concentrated in vacuo. The residue was dissolved in DMF (1.0 mL). 1M aq. NaOH soln. (1.0 mL) was added. The mixture was stirred at r.t. for 18 hours. The solution was neutralized with 1M aq. HCl soln. (1.0 mL), then purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 uM, acidic conditions, detection: UV/MS) to give the desired acid. LC-MS 1 FA: t_(R)=0.72 min; [M+H]⁺=529.1

Example 223 (±)-1-(2-Carboxymethoxy-5-[1, 2, 3]triazol-1-yl-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C27H24N4O5, MW=484.51) and Example 224 (±)-1-(2-Carboxymethoxy-5-[1, 2, 3]triazol-2-yl-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C27H24N4O5, MW=484.51)

1H-1,2,3-triazole (23 μL, 0.400 mmol, 2.00 eq.), copper (I) iodide (1.9 mg, 0.010 mmol, 0.05 eq.), cesium carbonate (130. mg, 0.400 mmol, 2.00 eq.) and N,N′-dimethyl-cyclohexane-1,2-diamine (7 μL, 0.040 mmol, 0.20 eq.) were added at r.t. to a solution of (±)-1-(5-bromo-2-ethoxycarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (105 mg, 0.200 mmol, 1.00 eq.) in DMF (0.1 mL) in a microwave tube. The tube was flushed with N₂, sealed, and heated to 120° C. for 60 hours. The reaction mixture was diluted with water and washed with AcOEt. The remaining aqueous phase was acidified with 1N aq. HCl and extracted with AcOEt (3×). The combined organic extracts were dried over MgSO₄, filtered and concentrated in vacuo. The crude residue, redissolved in DMF (1.2 mL), was purified by prep. HPLC (column: Atlantis, 19×50 mm, 5 um, UV/MS, acidic conditions) to give (±)-1-(2-carboxymethoxy-5-[1,2,3]triazol-1-yl-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (LC-MS 1FA: t_(R)=0.75 min; [M+H]⁺=485.2) and (±)-1-(2-carboxymethoxy-5-[1,2,3]triazol-2-yl-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (LC-MS 1FA: t_(R)=0.85 min; [M+H]⁺=485.1).

Example 225 (±)-{4-Chloro-2-[2-(2-methoxy-benzylthiocarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid (C26H25N2O4ClS, MW=497.01)

To a solution of (±)-[4-chloro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (76 mg, 0.20 mmol, 1.0 eq.) and N-ethyldiisopropylamine (42 μL, 0.24 mmol, 1.2 eq) in DCM (2 mL), 2-methoxybenzyl isothiocyanate (36 mg, 0.20 mmol, 1.0 eq.) was added. The resulting mixture was stirred at r.t. for 19 hours. The mixture was diluted with DCM (20 mL), washed with 10% aq. AcOH (2×5 mL) and with sat. aq. NaCl (1×5 mL). The org. layer was concentrated in vacuo. The residue was dissolved in DMF (1 mL). 1M aq. NaOH soln. (0.5 mL) was added. The mixture was stirred at r.t. for 7 hours. The solution was carefully neutralized with formic acid (0.5 mL), filtered, and purified by prep. HPLC (column: Waters X-bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) to give the desired acid as a white solid.

LC-MS 1 FA: t_(R)=0.89 min; [M+H]⁺=497.1

Example 226 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C25H21NO5ClF, MW=469.90)

A mixture under N₂ of (±)-1-(2-allyloxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (65 mg, 0.14 mmol, 1.00 eq.), 1,3-dimethylbarbituric acid (45 mg, 0.29 mmol, 2.00 eq.) and tetrakis(triphenylphosphine) palladium (0) (8.3 mg, 0.007 mmol, 0.05 eq.) in MeOH (3 mL) was stirred at r.t. for 3 hours. The mixture was partitioned between AcOEt (15 mL) and water (15 mL). The layers were separated and the aq. phase was extracted with AcOEt (2×15 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×15 mL), dried over MgSO₄, filtered, and concentrated in vacuo. To a solution of the residue and potassium carbonate anhydrous (60 mg, 0.43 mmol, 3.0 eq.) in DMF (2 mL), ethyl bromoacetate (48 μL, 0.43 mmol, 3.0 eq.) was added. The reaction mixture was stirred at r.t. during 2 hours. The reaction mixture was diluted with water (15 mL) and AcOEt (30 mL). The layers were separated. The aq. phase was extracted with AcOEt (2×15 mL). The comb. org. phases were washed with water (1×15 mL), sat. aq. NaCl soln. (1×15 mL), dried over MgSO₄, filtered, and concentrated in vacuo. To a solution of the residue in DMF (1.1 mL), 1M aq. NaOH (0.6 mL) was added. The resulting solution was stirred at r.t. for 24 hours. The solution was acidified with formic acid (0.6 mL). The crude product was purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the title compound.

LC-MS 3: t_(R)=0.95 min; [M+H]⁺=470.1

Saponification

To a solution of an ester of Structure 1 (0.10 mmol, 1 eq.) in THF (0.5 mL), 1M aq. NaOH (0.13 mL) was added. The resulting solution was stirred at r.t. for 14 hours. The org. solvent was removed in vacuo. The residue was diluted with water (2 mL) and acidified with 1M aq. HCl. The mixture was extracted with DCM (3×5 mL). The comb. org. phases were concentrated in vacuo. The crude product was purified by prep. HPLC (column: Waters X-Bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the desired acid as a white solid.

Listed in Table 17 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding compound of Structure 1 as starting material.

TABLE 17 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 227 (±)-1-(2-Carboxymethoxy-5- C25H21NO5BrCl 1.22 530.2 chloro-phenyl)-3,4-dihydro-1H- 530.80 LC-MS 1FA isoquinoline-2-carboxylic acid 2- bromo-benzyl ester 228 (S)-1-(2-Carboxymethoxy-5- C22H24NO5Cl 1.17 418.3 chloro-phenyl)-3,4-dihydro-1H- 417.89 LC-MS 1FA isoquinoline-2-carboxylic acid tert- butyl ester 229 (S)-1-(2-Carboxymethoxy-5- C25H20NO5ClF2 1.19 488.2 chloro-phenyl)-5,6-difluoro-3,4- 487.89 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid benzyl ester 230 (±)-1-(2-Carboxymethoxy-5- C24H20NO5Cl 1.09 438.2 chloro-phenyl)-1,3-dihydro- 437.88 LC-MS 1FA isoindole-2-carboxylic acid benzyl ester 231 1-(2-Carboxymethoxy-5-chloro- C24H20NO5Cl 1.09 438.2 phenyl)-1,3-dihydro-isoindole-2- 437.88 LC-MS 1FA carboxylic acid benzyl ester (enantiomer 1) 232 {4-Chloro-2-[(S)-2-((1R,2R)-2- C27H24NO4Cl 0.94 462.0 phenyl-cyclopropanecarbonyl)- 461.94 LC-MS 3 1,2,3,4-tetrahydro-isoquinolin-1- yl]-phenoxy}-acetic acid

Carbamate Formation and Saponification

Method A: To a solution of (±)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-nitro-phenyl ester (118 mg, 0.20 mmol, 1.0 eq.) and 2,4-dimethoxybenzyl alcohol (102 mg, 0.60 mmol, 3.0 eq.) in THF (4.5 mL), potassium tert-butoxide (67 mg, 0.60 mmol, 3.0 eq.) was added. The mixture was stirred at r.t. for 18 hours. The solvent was removed in vacuo (genevac). The residue was dissolved in MeCN/H₂O (1 mL, 1:1), formic acid (0.2 mL) was added followed by DMF (0.6 mL). The resulting solution was purified by prep. HPLC (column: Atlantis, 19×50 mm, 5 um, UV/MS, acidic conditions) to give the desired acid.

Listed in Table 18 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding 4-nitrophenol carbamate 7 and the corresponding alcohol as starting materials.

TABLE 18 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 233 (±)-1-(2-Carboxymethoxy-5- C26H24NO6Cl 0.96 481.7 chloro-phenyl)-3,4-dihydro-1H- 481.93 LC-MS 3 isoquinoline-2-carboxylic acid 2- methoxy-benzyl ester 234 (±)-1-(2-Carboxymethoxy-5- C25H21NO5ClF 1.15 470.2 chloro-phenyl)-3,4-dihydro-1H- 469.90 LC-MS 1FA isoquinoline-2-carboxylic acid 2- fluoro-benzyl ester 235 (±)-1-(2-Carboxymethoxy-5- C26H24NO5Cl 1.19 466.2 chloro-phenyl)-3,4-dihydro-1H- 465.93 LC-MS 1FA isoquinoline-2-carboxylic acid 2- methyl-benzyl ester 236 (±)-1-(2-Carboxymethoxy-5- C26H21NO5ClF3 1.22 520.2 chloro-phenyl)-3,4-dihydro-1H- 519.90 LC-MS 1FA isoquinoline-2-carboxylic acid 2- trifluoromethyl-benzyl ester 237 (±)-1-(2-Carboxymethoxy-5- C26H24NO6Cl 1.14 482.3 chloro-phenyl)-3,4-dihydro-1H- 481.93 LC-MS 1FA isoquinoline-2-carboxylic acid 3- methoxy-benzyl ester 238 (±)-1-(2-Carboxymethoxy-5- C25H21NO5ClF 1.15 470.2 chloro-phenyl)-3,4-dihydro-1H- 469.90 LC-MS 1FA isoquinoline-2-carboxylic acid 3- fluoro-benzyl ester 239 (±)-1-(2-Carboxymethoxy-5- C26H24NO5Cl 1.20 466.3 chloro-phenyl)-3,4-dihydro-1H- 465.93 LC-MS 1FA isoquinoline-2-carboxylic acid 3- methyl-benzyl ester 240 (±)-1-(2-Carboxymethoxy-5- C26H21NO5ClF3 1.22 520.2 chloro-phenyl)-3,4-dihydro-1H- 519.90 LC-MS 1FA isoquinoline-2-carboxylic acid 3- trifluoromethyl-benzyl ester 241 (±)-1-(2-Carboxymethoxy-5- C25H20NO5Cl3 1.28 520.1 chloro-phenyl)-3,4-dihydro-1H- 520.80 LC-MS 1FA isoquinoline-2-carboxylic acid 2,4- dichloro-benzyl ester 242 (±)-1-(2-Carboxymethoxy-5- C25H20NO5Cl3 1.25 520.1 chloro-phenyl)-3,4-dihydro-1H- 520.80 LC-MS 1FA isoquinoline-2-carboxylic acid 2,3- dichloro-benzyl ester 243 (±)-1-(2-Carboxymethoxy-5- C25H20NO5Cl3 1.21 520.2 chloro-phenyl)-3,4-dihydro-1H- 520.80 LC-MS 1FA isoquinoline-2-carboxylic acid 2,6- dichloro-benzyl ester 244 (±)-1-(2-Carboxymethoxy-5- C27H26NO7Cl 1.14 512.0 chloro-phenyl)-3,4-dihydro-1H- 511.96 LC-MS 1FA isoquinoline-2-carboxylic acid 2,6- dimethoxy-benzyl ester 245 (±)-1-(2-Carboxymethoxy-5- C27H26NO5Cl 1.24 480.1 chloro-phenyl)-3,4-dihydro-1H- 479.96 LC-MS 1FA isoquinoline-2-carboxylic acid 2,4- dimethyl-benzyl ester 246 (±)-1-(2-Carboxymethoxy-5- C27H26NO5Cl 1.23 480.2 chloro-phenyl)-3,4-dihydro-1H- 479.96 LC-MS 1FA isoquinoline-2-carboxylic acid 2,3- dimethyl-benzyl ester 247 (±)-1-(2-Carboxymethoxy-5- C27H26NO5Cl 1.21 480.1 chloro-phenyl)-3,4-dihydro-1H- 479.96 LC-MS 1FA isoquinoline-2-carboxylic acid 2,6- dimethyl-benzyl ester 248 (±)-1-(2-Carboxymethoxy-5- C25H20NO5ClF2 1.17 488.2 chloro-phenyl)-3,4-dihydro-1H- 487.89 LC-MS 1FA isoquinoline-2-carboxylic acid 2,4- difluoro-benzyl ester 249 (±)-1-(2-Carboxymethoxy-5- C25H20NO5ClF2 1.16 488.2 chloro-phenyl)-3,4-dihydro-1H- 487.89 LC-MS 1FA isoquinoline-2-carboxylic acid 2,3- difluoro-benzyl ester 250 (±)-1-(2-Carboxymethoxy-5- C25H20NO5ClF2 1.14 488.2 chloro-phenyl)-3,4-dihydro-1H- 487.89 LC-MS 1FA isoquinoline-2-carboxylic acid 2,6- difluoro-benzyl ester 251 (±)-1-(2-Carboxymethoxy-5- C28H28NO5Cl 1.27 494.2 chloro-phenyl)-3,4-dihydro-1H- 493.99 LC-MS 1FA isoquinoline-2-carboxylic acid 2,4,6-trimethyl-benzyl ester 252 (±)-1-(2-Carboxymethoxy-5- C25H20NO5Cl2F 1.18 504.2 chloro-phenyl)-3,4-dihydro-1H- 504.34 LC-MS 1FA isoquinoline-2-carboxylic acid 2- chloro-6-fluoro-benzyl ester 253 (±)-1-(2-Carboxymethoxy-5- C25H20NO5Cl3 1.26 520.1 chloro-phenyl)-3,4-dihydro-1H- 520.80 LC-MS 1FA isoquinoline-2-carboxylic acid 2,5- dichloro-benzyl ester 254 (±)-1-(2-Carboxymethoxy-5- C27H26NO7Cl 1.15 512.0 chloro-phenyl)-3,4-dihydro-1H- 511.96 LC-MS 1FA isoquinoline-2-carboxylic acid 2,4- dimethoxy-benzyl ester 255 (±)-1-(2-Carboxymethoxy-5- C27H26NO7Cl 1.14 512.2 chloro-phenyl)-3,4-dihydro-1H- 511.96 LC-MS 1FA isoquinoline-2-carboxylic acid 2,3- dimethoxy-benzyl ester 256 (±)-1-(2-Carboxymethoxy-5- C26H25N2O5Cl 0.73 481.3 chloro-phenyl)-3,4-dihydro-1H- 480.95 LC-MS 1FA isoquinoline-2-carboxylic acid 2,6- dimethyl-pyridin-3-ylmethyl ester 257 (±)-1-(2-Carboxymethoxy-5- C26H21N2O5Cl 1.09 477.2 chloro-phenyl)-3,4-dihydro-1H- 476.92 LC-MS 1FA isoquinoline-2-carboxylic acid 3- cyano-benzyl ester 258 (±)-1-(2-Carboxymethoxy-5- C25H20NO5ClF2 1.16 488.2 chloro-phenyl)-3,4-dihydro-1H- 487.89 LC-MS 1FA isoquinoline-2-carboxylic acid 2,5- difluoro-benzyl ester 259 (±)-1-(2-Carboxymethoxy-5- C25H20NO5Cl2F 1.21 504.1 chloro-phenyl)-3,4-dihydro-1H- 504.34 LC-MS 1FA isoquinoline-2-carboxylic acid 5- chloro-2-fluoro-benzyl ester 260 (±)-1-(2-Carboxymethoxy-5- C25H20NO5Cl2F 1.21 504.2 chloro-phenyl)-3,4-dihydro-1H- 504.34 LC-MS 1FA isoquinoline-2-carboxylic acid 2- chloro-5-fluoro-benzyl ester 261 (S)-1-(2-Carboxymethoxy-5- C26H24NO5Cl 1.17 466.3 chloro-phenyl)-3,4-dihydro-1H- 465.93 LC-MS 1FA isoquinoline-2-carboxylic acid (S)- 1-phenyl-ethyl ester 262 (±)-1-(2-Carboxymethoxy-5- C25H28NO5Cl 1.29 458.3 chloro-phenyl)-3,4-dihydro-1H- 457.95 LC-MS 1FA isoquinoline-2-carboxylic acid cyclohexylmethyl ester 263 (±)-1-(2-Carboxymethoxy-5- C23H22N3O5Cl 0.97 456.2 chloro-phenyl)-3,4-dihydro-1H- 455.90 LC-MS 1FA isoquinoline-2-carboxylic acid 1- methyl-1H-pyrazol-3-ylmethyl ester 264 (±)-1-(2-Carboxymethoxy-5- C24H26NO5Cl 1.25 444.3 chloro-phenyl)-3,4-dihydro-1H- 443.93 LC-MS 1FA isoquinoline-2-carboxylic acid cyclopentylmethyl ester 265 (±)-1-(2-Carboxymethoxy-5- C22H24NO5Cl 1.17 418.2 chloro-phenyl)-3,4-dihydro-1H- 417.89 LC-MS 1FA isoquinoline-2-carboxylic acid isobutyl ester 266 (±)-1-(2-Carboxymethoxy-5- C22H24NO5Cl 1.17 418.2 chloro-phenyl)-3,4-dihydro-1H- 417.89 LC-MS 1FA isoquinoline-2-carboxylic acid butyl ester 267 (±)-1-(2-Carboxymethoxy-5- C21H22NO6Cl 0.99 420.2 chloro-phenyl)-3,4-dihydro-1H- 419.86 LC-MS 1FA isoquinoline-2-carboxylic acid 2- methoxy-ethyl ester 268 (±)-1-(2-Carboxymethoxy-5- C22H22NO5Cl 1.12 416.2 chloro-phenyl)-3,4-dihydro-1H- 415.87 LC-MS 1FA isoquinoline-2-carboxylic acid cyclopropylmethyl ester 269 (±)-1-(2-Carboxymethoxy-5- C24H24N3O5Cl 1.03 470.3 chloro-phenyl)-3,4-dihydro-1H- 469.92 LC-MS 1FA isoquinoline-2-carboxylic acid 3,5- dimethyl-pyrazol-1-ylmethyl ester 270 (±)-1-(2-Carboxymethoxy-5- C23H21N2O6Cl 1.04 457.2 chloro-phenyl)-3,4-dihydro-1H- 456.88 LC-MS 1FA isoquinoline-2-carboxylic acid 5- methyl-isoxazol-3-ylmethyl ester 271 (±)-1-(2-Carboxymethoxy-5- C24H24N3O5Cl 1.00 470.3 chloro-phenyl)-3,4-dihydro-1H- 469.92 LC-MS 1FA isoquinoline-2-carboxylic acid 1,5- dimethyl-1H-pyrazol-3-ylmethyl ester 272 (±)-1-(2-Carboxymethoxy-5- C25H21NO5Cl2 1.21 486.2 chloro-phenyl)-3,4-dihydro-1H- 486.35 LC-MS 1FA isoquinoline-2-carboxylic acid 4- chloro-benzyl ester 273 (S)-1-(2-Carboxymethoxy-5- C22H19N2O5ClS 0.88 459.1 chloro-phenyl)-3,4-dihydro-1H- 458.92 LC-MS 3 isoquinoline-2-carboxylic acid thiazol-2-ylmethyl ester 274 (S)-1-(2-Carboxymethoxy-5- C24H23N2O5ClS 1.01 487.2 chloro-phenyl)-3,4-dihydro-1H- 486.98 LC-MS 1FA isoquinoline-2-carboxylic acid 2- (4-methyl-thiazol-5-yl)-ethyl ester 275 (S)-1-(2-Carboxymethoxy-5- C23H21N2O5ClS 1.06 473.2 chloro-phenyl)-3,4-dihydro-1H- 472.95 LC-MS 1FA isoquinoline-2-carboxylic acid 5- methyl-thiazol-2-ylmethyl ester 276 (S)-1-(2-Carboxymethoxy-5- C23H21N2O5ClS 1.05 473.2 chloro-phenyl)-3,4-dihydro-1H- 472.95 LC-MS 1FA isoquinoline-2-carboxylic acid 4- methyl-thiazol-2-ylmethyl ester 277 (S)-1-(2-Carboxymethoxy-5- C23H21N2O5ClS 1.01 473.2 chloro-phenyl)-3,4-dihydro-1H- 472.95 LC-MS 1FA isoquinoline-2-carboxylic acid 2- methyl-thiazol-5-ylmethyl ester 278 (S)-1-(2-Carboxymethoxy-5- C23H21N2O5ClS 1.03 473.2 chloro-phenyl)-3,4-dihydro-1H- 472.95 LC-MS 1FA isoquinoline-2-carboxylic acid 2- methyl-thiazol-4-ylmethyl ester 279 (S)-1-(2-Carboxymethoxy-5- C23H21N2O6Cl 1.02 457.1 chloro-phenyl)-3,4-dihydro-1H- 456.88 LC-MS 1FA isoquinoline-2-carboxylic acid 3- methyl-isoxazol-5-ylmethyl ester 280 (S)-1-(2-Carboxymethoxy-5- C23H21N2O6Cl 0.89 457.2 chloro-phenyl)-3,4-dihydro-1H- 456.88 LC-MS 3 isoquinoline-2-carboxylic acid 4- methyl-isoxazol-3-ylmethyl ester 281 (S)-1-(2-Carboxymethoxy-5- C24H23N2O6Cl 0.90 471.2 chloro-phenyl)-3,4-dihydro-1H- 470.91 LC-MS 3 isoquinoline-2-carboxylic acid 3,5- dimethyl-isoxazol-4-ylmethyl ester 282 (S)-1-(2-Carboxymethoxy-5- C23H20N3O5Cl 0.85 454.2 chloro-phenyl)-3,4-dihydro-1H- 453.88 LC-MS 3 isoquinoline-2-carboxylic acid pyrazin-2-ylmethyl ester 283 (S)-1-(2-Carboxymethoxy-5- C23H20N3O5Cl 0.85 454.2 chloro-phenyl)-3,4-dihydro-1H- 453.88 LC-MS 3 isoquinoline-2-carboxylic acid pyrimidin-4-ylmethyl ester 284 (S)-1-(2-Carboxymethoxy-5- C23H20N3O5Cl 0.85 454.2 chloro-phenyl)-3,4-dihydro-1H- 453.88 LC-MS 3 isoquinoline-2-carboxylic acid pyrimidin-5-ylmethyl ester 285 (S)-1-(2-Carboxymethoxy-5- C26H24NO5Cl 1.20 466.3 chloro-phenyl)-3,4-dihydro-1H- 465.93 LC-MS 1FA isoquinoline-2-carboxylic acid phenethyl ester 286 (S)-1-(2-Carboxymethoxy-5- C26H23NO5ClF 0.98 484.2 chloro-phenyl)-3,4-dihydro-1H- 483.92 LC-MS 3 isoquinoline-2-carboxylic acid 2- (3-fluoro-phenyl)-ethyl ester 287 (S)-1-(2-Carboxymethoxy-5- C23H22N3O5Cl 0.96 456.2 chloro-phenyl)-3,4-dihydro-1H- 455.90 LC-MS 1FA isoquinoline-2-carboxylic acid 2- methyl-2H-pyrazol-3-ylmethyl ester 288 (S)-1-(2-Carboxymethoxy-5- C24H24N3O5Cl 0.99 470.2 chloro-phenyl)-3,4-dihydro-1H- 469.92 LC-MS 1FA isoquinoline-2-carboxylic acid 2,5- dimethyl-2H-pyrazol-3-ylmethyl ester 289 (S)-1-(2-Carboxymethoxy-5- C26H28N3O5Cl 0.84 498.0 chloro-phenyl)-3,4-dihydro-1H- 497.98 LC-MS 3 isoquinoline-2-carboxylic acid 2- (2-ethyl-5-methyl-2H-pyrazol-3-yl)- ethyl ester 290 (S)-1-(2-Carboxymethoxy-5- C23H22N3O5Cl 0.69 456.2 chloro-phenyl)-3,4-dihydro-1H- 455.90 LC-MS 3 isoquinoline-2-carboxylic acid 3- methyl-3H-imidazol-4-ylmethyl ester 291 (S)-1-(2-Carboxymethoxy-5- C25H26N3O5Cl 0.85 484.2 chloro-phenyl)-3,4-dihydro-1H- 483.95 LC-MS 3 isoquinoline-2-carboxylic acid 2- (3,5-dimethyl-pyrazol-1-yl)-ethyl ester 292 (S)-1-(2-Carboxymethoxy-5- C23H22N3O5Cl 1.02 456.2 chloro-phenyl)-3,4-dihydro-1H- 455.90 LC-MS 1FA isoquinoline-2-carboxylic acid 4- methyl-pyrazol-1-ylmethyl ester 293 (S)-1-(2-Carboxymethoxy-5- C28H26N3O5Cl 0.83 520.3 chloro-phenyl)-3,4-dihydro-1H- 519.98 LC-MS isoquinoline-2-carboxylic acid 2- 1TFA (2-methyl-benzoimidazol-1-yl)- ethyl ester 294 (S)-1-(2-Carboxymethoxy-5- C26H21N2O5ClS 1.15 509.2 chloro-phenyl)-3,4-dihydro-1H- 508.98 LC-MS 1FA isoquinoline-2-carboxylic acid benzothiazol-2-ylmethyl ester 295 (S)-1-(2-Carboxymethoxy-5- C26H21N2O6Cl 0.93 493.2 chloro-phenyl)-3,4-dihydro-1H- 492.91 LC-MS 3 isoquinoline-2-carboxylic acid benzooxazol-2-ylmethyl ester 296 (S)-1-(2-Carboxymethoxy-5- C27H24N3O5Cl 1.11 506.3 chloro-phenyl)-3,4-dihydro-1H- 505.96 LC-MS 1FA isoquinoline-2-carboxylic acid 1- methyl-1H-indazol-3-ylmethyl ester 297 (S)-1-(2-Carboxymethoxy-5- C26H22N3O5Cl 1.09 492.2 chloro-phenyl)-3,4-dihydro-1H- 491.93 LC-MS 1FA isoquinoline-2-carboxylic acid indazol-1-ylmethyl ester 298 (S)-1-(2-Carboxymethoxy-5- C26H21N2O6Cl 0.95 493.2 chloro-phenyl)-3,4-dihydro-1H- 492.91 LC-MS 3 isoquinoline-2-carboxylic acid benzo[d]isoxazol-3-ylmethyl ester 299 (S)-1-(2-Carboxymethoxy-5- C22H17N2O5ClF2S 1.05 495.2 chloro-phenyl)-5,6-difluoro-3,4- 494.90 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid thiazol-2-ylmethyl ester 300 (S)-1-(2-Carboxymethoxy-5- C24H21N2O5ClF2S 0.90 523.1 chloro-phenyl)-5,6-difluoro-3,4- 522.96 LC-MS 3 dihydro-1H-isoquinoline-2- carboxylic acid 2-(4-methyl- thiazol-5-yl)-ethyl ester 301 (S)-1-(2-Carboxymethoxy-5- C23H19N2O5ClF2S 0.93 509.1 chloro-phenyl)-5,6-difluoro-3,4- 508.93 LC-MS 3 dihydro-1H-isoquinoline-2- carboxylic acid 5-methyl-thiazol-2- ylmethyl ester 302 (S)-1-(2-Carboxymethoxy-5- C23H19N2O5ClF2S 1.09 509.2 chloro-phenyl)-5,6-difluoro-3,4- 508.93 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid 4-methyl-thiazol-2- ylmethyl ester 303 (S)-1-(2-Carboxymethoxy-5- C23H19N2O5ClF2S 0.92 509.1 chloro-phenyl)-5,6-difluoro-3,4- 508.93 LC-MS 3 dihydro-1H-isoquinoline-2- carboxylic acid 2-methyl-thiazol-5- ylmethyl ester 304 (S)-1-(2-Carboxymethoxy-5- C23H19N2O5ClF2S 1.07 509.2 chloro-phenyl)-5,6-difluoro-3,4- 508.93 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid 2-methyl-thiazol-4- ylmethyl ester 305 (S)-1-(2-Carboxymethoxy-5- C23H19N2O6ClF2 0.91 493.2 chloro-phenyl)-5,6-difluoro-3,4- 492.86 LC-MS 3 dihydro-1H-isoquinoline-2- carboxylic acid 3-methyl-isoxazol- 5-ylmethyl ester 306 (S)-1-(2-Carboxymethoxy-5- C23H19N2O6ClF2 0.92 493.2 chloro-phenyl)-5,6-difluoro-3,4- 492.86 LC-MS 3 dihydro-1H-isoquinoline-2- carboxylic acid 4-methyl-isoxazol- 3-ylmethyl ester 307 (S)-1-(2-Carboxymethoxy-5- C24H21N2O6ClF2 0.92 507.1 chloro-phenyl)-5,6-difluoro-3,4- 506.89 LC-MS 3 dihydro-1H-isoquinoline-2- carboxylic acid 3,5-dimethyl- isoxazol-4-ylmethyl ester 308 (S)-1-(2-Carboxymethoxy-5- C23H18N3O5ClF2 0.88 490.2 chloro-phenyl)-5,6-difluoro-3,4- 489.86 LC-MS 3 dihydro-1H-isoquinoline-2- carboxylic acid pyrazin-2-ylmethyl ester 309 (S)-1-(2-Carboxymethoxy-5- C23H18N3O5ClF2 0.89 490.2 chloro-phenyl)-5,6-difluoro-3,4- 489.86 LC-MS 3 dihydro-1H-isoquinoline-2- carboxylic acid pyrimidin-4- ylmethyl ester 310 (S)-1-(2-Carboxymethoxy-5- C26H22NO5ClF2 0.99 502.2 chloro-phenyl)-5,6-difluoro-3,4- 501.91 LC-MS 3 dihydro-1H-isoquinoline-2- carboxylic acid phenethyl ester 311 (S)-1-(2-Carboxymethoxy-5- C26H21NO5ClF3 0.99 520.1 chloro-phenyl)-5,6-difluoro-3,4- 519.90 LC-MS 3 dihydro-1H-isoquinoline-2- carboxylic acid 2-(3-fluoro- phenyl)-ethyl ester 312 (S)-1-(2-Carboxymethoxy-5- C23H20N3O5ClF2 1.01 492.2 chloro-phenyl)-5,6-difluoro-3,4- 491.88 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid 2-methyl-2H- pyrazol-3-ylmethyl ester 313 (S)-1-(2-Carboxymethoxy-5- C24H22N3O5ClF2 0.90 506.2 chloro-phenyl)-5,6-difluoro-3,4- 505.90 LC-MS 3 dihydro-1H-isoquinoline-2- carboxylic acid 2,5-dimethyl-2H- pyrazol-3-ylmethyl ester 314 (S)-1-(2-Carboxymethoxy-5- C26H26N3O5ClF2 1.06 534.3 chloro-phenyl)-5,6-difluoro-3,4- 533.96 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid 2-(2-ethyl-5- methyl-2H-pyrazol-3-yl)-ethyl ester 315 (S)-1-(2-Carboxymethoxy-5- C23H20N3O5ClF2 0.72 492.2 chloro-phenyl)-5,6-difluoro-3,4- 491.88 LC-MS 3 dihydro-1H-isoquinoline-2- carboxylic acid 3-methyl-3H- imidazol-4-ylmethyl ester 316 (S)-1-(2-Carboxymethoxy-5- C25H24N3O5ClF2 0.87 520.2 chloro-phenyl)-5,6-difluoro-3,4- 519.93 LC-MS 3 dihydro-1H-isoquinoline-2- carboxylic acid 2-(3,5-dimethyl- pyrazol-1-yl)-ethyl ester 317 (S)-1-(2-Carboxymethoxy-5- C23H20N3O5ClF2 0.90 492.1 chloro-phenyl)-5,6-difluoro-3,4- 491.88 LC-MS 3 dihydro-1H-isoquinoline-2- carboxylic acid 4-methyl-pyrazol- 1-ylmethyl ester 318 (S)-1-(2-Carboxymethoxy-5- C28H24N3O5ClF2 0.86 556.3 chloro-phenyl)-5,6-difluoro-3,4- 555.96 LC-MS dihydro-1H-isoquinoline-2- 1TFA carboxylic acid 2-(2-methyl- benzoimidazol-1-yl)-ethyl ester 319 (S)-1-(2-Carboxymethoxy-5- C26H19N2O5ClF2S 1.18 545.1 chloro-phenyl)-5,6-difluoro-3,4- 544.96 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid benzothiazol-2- ylmethyl ester 320 (S)-1-(2-Carboxymethoxy-5- C26H19N2O6ClF2 0.95 529.0 chloro-phenyl)-5,6-difluoro-3,4- 528.89 LC-MS 3 dihydro-1H-isoquinoline-2- carboxylic acid benzooxazol-2- ylmethyl ester 321 (S)-1-(2-Carboxymethoxy-5- C27H22N3O5ClF2 1.14 542.3 chloro-phenyl)-5,6-difluoro-3,4- 541.94 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid 1-methyl-1H- indazol-3-ylmethyl ester 322 (S)-1-(2-Carboxymethoxy-5- C26H20N3O5ClF2 0.94 528.1 chloro-phenyl)-5,6-difluoro-3,4- 527.91 LC-MS 3 dihydro-1H-isoquinoline-2- carboxylic acid indazol-1-ylmethyl ester 323 (S)-1-(2-Carboxymethoxy-5- C26H19N2O6ClF2 0.96 529.0 chloro-phenyl)-5,6-difluoro-3,4- 528.89 LC-MS 3 dihydro-1H-isoquinoline-2- carboxylic acid benzo[d]isoxazol- 3-ylmethyl ester 324 (S)-1-(2-Carboxymethoxy-5- C22H18N2O5ClFS 1.02 477.2 chloro-phenyl)-6-fluoro-3,4- 476.91 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid thiazol-2-ylmethyl ester 325 (S)-1-(2-Carboxymethoxy-5- C24H22N2O5ClFS 1.02 505.2 chloro-phenyl)-6-fluoro-3,4- 504.97 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid 2-(4-methyl- thiazol-5-yl)-ethyl ester 326 (S)-1-(2-Carboxymethoxy-5- C23H20N2O5ClFS 1.07 491.2 chloro-phenyl)-6-fluoro-3,4- 490.94 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid 5-methyl-thiazol-2- ylmethyl ester 327 (S)-1-(2-Carboxymethoxy-5- C23H20N2O5ClFS 1.06 491.2 chloro-phenyl)-6-fluoro-3,4- 490.94 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid 4-methyl-thiazol-2- ylmethyl ester 328 (S)-1-(2-Carboxymethoxy-5- C23H20N2O5ClFS 1.02 491.2 chloro-phenyl)-6-fluoro-3,4- 490.94 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid 2-methyl-thiazol-5- ylmethyl ester 329 (S)-1-(2-Carboxymethoxy-5- C23H20N2O5ClFS 1.04 491.2 chloro-phenyl)-6-fluoro-3,4- 490.94 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid 2-methyl-thiazol-4- ylmethyl ester 330 (S)-1-(2-Carboxymethoxy-5- C23H20N2O6ClF 1.03 475.2 chloro-phenyl)-6-fluoro-3,4- 474.87 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid 3-methyl-isoxazol- 5-ylmethyl ester 331 (S)-1-(2-Carboxymethoxy-5- C23H20N2O6ClF 0.90 475.2 chloro-phenyl)-6-fluoro-3,4- 474.87 LC-MS 3 dihydro-1H-isoquinoline-2- carboxylic acid 4-methyl-isoxazol- 3-ylmethyl ester 332 (S)-1-(2-Carboxymethoxy-5- C23H19N3O5ClF 0.96 472.2 chloro-phenyl)-6-fluoro-3,4- 471.87 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid pyrazin-2-ylmethyl ester 333 (S)-1-(2-Carboxymethoxy-5- C23H19N3O5ClF 0.94 472.2 chloro-phenyl)-6-fluoro-3,4- 471.87 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid pyrimidin-4- ylmethyl ester 334 (S)-1-(2-Carboxymethoxy-5- C23H19N3O5ClF 0.86 472.2 chloro-phenyl)-6-fluoro-3,4- 471.87 LC-MS 3 dihydro-1H-isoquinoline-2- carboxylic acid pyrimidin-5- ylmethyl ester 335 (S)-1-(2-Carboxymethoxy-5- C26H23NO5ClF 1.20 484.2 chloro-phenyl)-6-fluoro-3,4- 483.92 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid phenethyl ester 336 (S)-1-(2-Carboxymethoxy-5- C26H22NO5ClF2 0.98 502.2 chloro-phenyl)-6-fluoro-3,4- 501.91 LC-MS 3 dihydro-1H-isoquinoline-2- carboxylic acid 2-(3-fluoro- phenyl)-ethyl ester 337 (S)-1-(2-Carboxymethoxy-5- C23H21N3O5ClF 0.98 474.2 chloro-phenyl)-6-fluoro-3,4- 473.89 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid 2-methyl-2H- pyrazol-3-ylmethyl ester 338 (S)-1-(2-Carboxymethoxy-5- C24H23N3O5ClF 1.00 488.3 chloro-phenyl)-6-fluoro-3,4- 487.91 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid 2,5-dimethyl-2H- pyrazol-3-ylmethyl ester 339 (S)-1-(2-Carboxymethoxy-5- C26H27N3O5ClF 0.85 516.2 chloro-phenyl)-6-fluoro-3,4- 515.97 LC-MS 3 dihydro-1H-isoquinoline-2- carboxylic acid 2-(2-ethyl-5- methyl-2H-pyrazol-3-yl)-ethyl ester 340 (S)-1-(2-Carboxymethoxy-5- C23H21N3O5ClF 0.71 474.2 chloro-phenyl)-6-fluoro-3,4- 473.89 LC-MS 3 dihydro-1H-isoquinoline-2- carboxylic acid 3-methyl-3H- imidazol-4-ylmethyl ester 341 (S)-1-(2-Carboxymethoxy-5- C25H25N3O5ClF 1.04 502.3 chloro-phenyl)-6-fluoro-3,4- 501.94 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid 2-(3,5-dimethyl- pyrazol-1-yl)-ethyl ester 342 (S)-1-(2-Carboxymethoxy-5- C23H21N3O5ClF 0.89 474.2 chloro-phenyl)-6-fluoro-3,4- 473.89 LC-MS 3 dihydro-1H-isoquinoline-2- carboxylic acid 4-methyl-pyrazol- 1-ylmethyl ester 343 (S)-1-(2-Carboxymethoxy-5- C28H25N3O5ClF 0.84 538.3 chloro-phenyl)-6-fluoro-3,4- 537.97 LC-MS dihydro-1H-isoquinoline-2- 1TFA carboxylic acid 2-(2-methyl- benzoimidazol-1-yl)-ethyl ester 344 (S)-1-(2-Carboxymethoxy-5- C26H20N2O5ClFS 1.15 527.2 chloro-phenyl)-6-fluoro-3,4- 526.97 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid benzothiazol-2- ylmethyl ester 345 (S)-1-(2-Carboxymethoxy-5- C26H20N2O6ClF 0.94 511.1 chloro-phenyl)-6-fluoro-3,4- 510.90 LC-MS 3 dihydro-1H-isoquinoline-2- carboxylic acid benzooxazol-2- ylmethyl ester 346 (S)-1-(2-Carboxymethoxy-5- C27H23N3O5ClF 1.11 524.3 chloro-phenyl)-6-fluoro-3,4- 523.95 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid 1-methyl-1H- indazol-3-ylmethyl ester 347 (S)-1-(2-Carboxymethoxy-5- C26H21N3O5ClF 0.93 510.1 chloro-phenyl)-6-fluoro-3,4- 509.92 LC-MS 3 dihydro-1H-isoquinoline-2- carboxylic acid indazol-1-ylmethyl ester 348 (S)-1-(2-Carboxymethoxy-5- C26H20N2O6ClF 0.95 511.1 chloro-phenyl)-6-fluoro-3,4- 510.90 LC-MS 3 dihydro-1H-isoquinoline-2- carboxylic acid benzo[d]isoxazol- 3-ylmethyl ester

Method B: To a solution of [4-chloro-2-((S)-5,6-difluoro-1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (91 mg, 0.21 mmol, 1 eq.) and DIPEA (90 μL, 0.53 mmol, 2.5 eq.) in DCM (3.3 mL), carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester 2-fluoro-benzyl ester (70 mg, 0.25 mmol, 1.2 eq.) was added. The mixture was stirred at r.t. for 1 hour. The reaction was quenched with 1M aq. citric acid soln. (3.3 mL). The layers were separated. The aq. phase was extracted with DCM (3×5 mL). The comb. org. phases were concentrated in vacuo (genevac). To a solution of the residue in DMF (1 mL), 1M aq. NaOH (0.55 mL) was added. The solution was stirred at r.t. for 1 hour. Formic acid (0.1 mL) was added. The resulting acidic solution was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated (genevac) to give the desired acid.

Listed in Table 19 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding amine of Structure 2 and the corresponding carbonate 5 as starting materials.

TABLE 19 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 349 (S)-1-(2-Carboxymethoxy-5- C25H19NO5ClF3 1.19 506.2 chloro-phenyl)-5,6-difluoro-3,4- 505.88 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid 2-fluoro-benzyl ester 350 (S)-1-(2-Carboxymethoxy-5- C25H19NO5ClF3 1.19 506.1 chloro-phenyl)-5,6-difluoro-3,4- 505.88 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid 3-fluoro-benzyl ester 351 (S)-1-(2-Carboxymethoxy-5- C25H18NO5ClF4 1.19 524.2 chloro-phenyl)-5,6-difluoro-3,4- 523.87 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid 2,3-difluoro-benzyl ester 352 (S)-1-(2-Carboxymethoxy-5- C25H20NO5ClF2 1.16 488.2 chloro-phenyl)-6-fluoro-3,4- 487.89 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid 2-fluoro-benzyl ester 353 (S)-1-(2-Carboxymethoxy-5- C25H20NO5ClF2 1.16 488.2 chloro-phenyl)-6-fluoro-3,4- 487.89 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid 3-fluoro-benzyl ester 354 (S)-1-(2-Carboxymethoxy-5- C25H19NO5ClF3 1.17 506.2 chloro-phenyl)-6-fluoro-3,4- 505.88 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid 2,3-difluoro-benzyl ester 355 (S)-1-(2-Carboxymethoxy-5- C25H21NO5ClF 1.15 470.2 chloro-phenyl)-3,4-dihydro-1H- 469.90 LC-MS 1FA isoquinoline-2-carboxylic acid 3- fluoro-benzyl ester 356 (S)-1-(2-Carboxymethoxy-5- C26H24NO6Cl 1.16 482.1 chloro-phenyl)-3,4-dihydro-1H- 481.93 LC-MS 1FA isoquinoline-2-carboxylic acid 2- methoxy-benzyl ester 357 (S)-1-(2-Carboxymethoxy-5- C25H21NO5ClF 1.15 470.2 chloro-phenyl)-3,4-dihydro-1H- 469.90 LC-MS 1FA isoquinoline-2-carboxylic acid 2- fluoro-benzyl ester 358 (S)-1-(2-Carboxymethoxy-5- C25H20NO5ClF2 1.17 488.1 chloro-phenyl)-5-fluoro-3,4- 487.89 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid 3-fluoro-benzyl ester 359 (S)-1-(2-Carboxymethoxy-5- C25H20NO5ClF2 1.17 488.2 chloro-phenyl)-5-fluoro-3,4- 487.89 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid 2-fluoro-benzyl ester 360 (±)-1-(2-Carboxymethoxy-5- C26H24NO5Cl 1.20 466.2 chloro-phenyl)-3,4-dihydro-1H- 465.93 LC-MS 1FA isoquinoline-2-carboxylic acid 4- methyl-benzyl ester 361 (±)-1-(2-Carboxymethoxy-5- C26H24NO6Cl 1.14 482.2 chloro-phenyl)-3,4-dihydro-1H- 481.93 LC-MS 1FA isoquinoline-2-carboxylic acid 4- methoxy-benzyl ester 362 (±)-1-(2-Carboxymethoxy-5- C25H21NO5ClF 1.15 470.2 chloro-phenyl)-3,4-dihydro-1H- 469.90 LC-MS 1FA isoquinoline-2-carboxylic acid 4- fluoro-benzyl ester 363 (±)-1-(2-Carboxymethoxy-5- C26H21NO5ClF3 1.23 520.2 chloro-phenyl)-3,4-dihydro-1H- 519.90 LC-MS 1FA isoquinoline-2-carboxylic acid 4- trifluoromethyl-benzyl ester 364 (±)-1-(2-Carboxymethoxy-5- C25H21NO5Cl2 1.21 486.2 chloro-phenyl)-3,4-dihydro-1H- 486.35 LC-MS 1FA isoquinoline-2-carboxylic acid 3- chloro-benzyl ester

Method C: To an-ice cooled solution of (±)-[4-chloro-2-(7-fluoro-1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (378 mg, 0.94 mmol, 1.0 eq.) and NEt₃ (0.39 mL, 2.83 mmol, 3.0 eq.) in DCM (10 mL), benzyl chloroformate (0.17 mL, 1.13 mmol, 1.2 eq.) was added. The solution was stirred at 0° C. for 1 hour and further at r.t. for 4 hours. The reaction was diluted with DCM (10 mL) and quenched with 1M aq. citric acid soln. (20 mL). The layers were separated. The aq. phase was extracted with DCM (3×10 mL). The comb. org. phases were dried over Na₂SO₄ and concentrated in vacuo. To a solution of the residue in DMF (3 mL), 1M aq. NaOH (1.5 mL) was added. The resulting mixture was stirred at r.t. for 18 hours. The reaction mixture was neutralized with formic acid (ca. 1.5 mL) and purified by prep. HPLC (column: Water X-Bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid.

Listed in Table 20 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding amine of Structure 2 as starting material.

TABLE 20 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 365 (±)-1-(2-Carboxymethoxy-5- C25H21NO5ClF 1.15 470.2 chloro-phenyl)-7-fluoro-3,4- 469.90 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid benzyl ester 366 (±)-1-(2-Carboxymethoxy-phenyl)- C25H23NO5 1.09 418.3 3,4-dihydro-1H-isoquinoline-2- 417.46 LC-MS 1FA carboxylic acid benzyl ester 367 (S)-1-(2-Carboxymethoxy-5- C25H21NO5ClF 1.16 470.2 chloro-phenyl)-6-fluoro-3,4- 469.90 LC-MS 1FA dihydro-1H-isoquinoline-2- carboxylic acid benzyl ester

Michael Addition and Subsequent Saponification

Potassium fluoride 40 wt. % on alumina (216 mg, 3.72 mmol, 17.2 eq.) was added to a mixture of (±)-[2-(2-acryloyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-4-chloro-phenoxy]-acetic acid ethyl ester (100 mg, 0.22 mmol, 1.0 eq.) and 5-fluoro-3-methylindole (33 mg, 0.22 mmol, 1.0 eq.) in MeCN (1 mL). The resulting suspension was stirred at 80° C. for 18 hours. Formic acid was added (0.2 mL). The reaction mixture was filtered and the filtrate purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired product as a white foam.

Listed in Table 21 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding vinyl amide 8 and the corresponding heterocycle 9 as starting materials.

TABLE 21 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 368 (±)-(4-Chloro-2-{2-[3-(5-fluoro-3- C29H26NO4ClF 1.19 521.3 methyl-indol-1-yl)-propionyl]- 520.99 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- yl}-phenoxy)-acetic acid 369 (±)-{4-Chloro-2-[2-(3-pyrrolo[2,3- C27H24N3O4Cl 1.01 490.3 b]pyridin-1-yl-propionyl)-1,2,3,4- 489.96 LC-MS 1FA tetrahydro-isoquinolin-1-yl]- phenoxy}-acetic acid 370 (±)-(4-Chloro-2-{2-[3-(6- C29H24N2O4ClF3 1.23 557.1 trifluoromethyl-indol-1-yl)- 556.97 LC-MS 1FA propionyl]-1,2,3,4-tetrahydro- isoquinolin-1-yl}-phenoxy)-acetic acid 371 (±)-(4-Chloro-2-{2-[3-(5-cyano- C29H24N3O4Cl 1.06 514.2 indol-1-yl)-propionyl]-1,2,3,4- 513.98 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 372 (±)-{4-Chloro-2-[2-(3-pyrrolo[2,3- C27H24N3O4Cl 0.70 490.0 c]pyridin-1-yl-propionyl)-1,2,3,4- 489.96 LC-MS 1FA tetrahydro-isoquinolin-1-yl]- phenoxy}-acetic acid 373 (±)-(4-Chloro-2-{2-[3-(6-methoxy- C28H26N3O5Cl 0.70 520.3 pyrrolo[3,2-c]pyridin-1-yl)- 519.98 LC-MS 1FA propionyl]-1,2,3,4-tetrahydro- isoquinolin-1-yl}-phenoxy)-acetic acid 374 (±)-(4-Chloro-2-{2-[3-(6-methoxy- C28H26N3O5Cl 1.15 520.3 pyrrolo[2,3-b]pyridin-1-yl)- 519.98 LC-MS 1FA propionyl]-1,2,3,4-tetrahydro- isoquinolin-1-yl}-phenoxy)-acetic acid 375 (±)-(4-Chloro-2-{2-[3-(5-chloro-6- C29H26N2O5Cl2 1.17 553.1 methoxy-indol-1-yl)-propionyl]- 553.44 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- yl}-phenoxy)-acetic acid 376 (±)-(4-Chloro-2-{2-[3-(4,6- C29H28N3O6Cl 1.12 550.3 dimethoxy-pyrrolo[2,3-b]pyridin-1- 550.01 LC-MS 1FA yl)-propionyl]-1,2,3,4-tetrahydro- isoquinolin-1-yl}-phenoxy)-acetic acid 377 (±)-(4-Chloro-2-{2-[3-(4,6- C30H29N2O6Cl 1.11 549.3 dimethoxy-indol-1-yl)-propionyl]- 549.02 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- yl}-phenoxy)-acetic acid 378 (±)-{4-Chloro-2-[2-(3-indol-1-yl- C28H25N2O4Cl 1.15 489.3 propionyl)-1,2,3,4-tetrahydro- 488.97 LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic acid 379 (±)-(4-Chloro-2-{2-[3-(5-fluoro- C28H24N2O4ClF 1.14 507.3 indol-1-yl)-propionyl]-1,2,3,4- 506.96 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 380 (±)-(4-Chloro-2-{2-[3-(7-chloro- C28H24N2O4Cl2 1.21 523.1 indol-1-yl)-propionyl]-1,2,3,4- 523.42 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 381 (±)-{4-Chloro-2-[2-(3-pyrrolo[3,2- C27H24N3O4Cl 0.66 490.3 b]pyridin-1-yl-propionyl)-1,2,3,4- 489.96 LC-MS 1FA tetrahydro-isoquinolin-1-yl]- phenoxy}-acetic acid 382 (±)-(4-Chloro-2-{2-[3-(4-methoxy- C29H27N2O5Cl 1.12 519.3 indol-1-yl)-propionyl]-1,2,3,4- 519.00 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 383 (±)-(4-Chloro-2-{2-[3-(3-chloro- C27H23N3O4Cl2 1.16 524.2 indazol-1-yl)-propionyl]-1,2,3,4- 524.40 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 384 (±)-(4-Chloro-2-{2-[3-(6-methyl- C29H27N2O4Cl 1.19 503.3 indol-1-yl)-propionyl]-1,2,3,4- 503.00 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 385 (±)-(4-Chloro-2-{2-[3-(5-chloro- C28H24N2O4Cl2 1.20 523.1 indol-1-yl)-propionyl]-1,2,3,4- 523.42 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 386 (±)-(4-Chloro-2-{2-[3-(6-chloro- C28H24N2O4Cl2 1.20 523.3 indol-1-yl)-propionyl]-1,2,3,4- 523.42 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 387 (±)-(4-Chloro-2-{2-[3-(4-fluoro- C28H24N2O4ClF 1.15 507.2 indol-1-yl)-propionyl]-1,2,3,4- 506.96 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 388 (±)-(4-Chloro-2-{2-[3-(6-fluoro- C28H24N2O4ClF 1.15 507.3 indol-1-yl)-propionyl]-1,2,3,4- 506.96 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 389 (±)-(4-Chloro-2-{2-[3-(2,3- C30H29N2O4Cl 1.23 517.3 dimethyl-indol-1-yl)-propionyl]- 517.02 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- yl}-phenoxy)-acetic acid 390 (±)-(4-Chloro-2-{2-[3-(6-methoxy- C29H27N2O5Cl 1.13 519.3 indol-1-yl)-propionyl]-1,2,3,4- 519.00 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 391 (4-Chloro-2-{(S)-6-fluoro-2-[3-(4- C28H24N3O4ClF2 1.11 540.3 fluoro-3-methyl-indazol-1-yl)- 539.97 LC-MS 1FA propionyl]-1,2,3,4-tetrahydro- isoquinolin-1-yl}-phenoxy)-acetic acid 392 (4-Chloro-2-{(S)-6-fluoro-2-[3-(7- C28H24N3O4ClF2 1.11 540.3 fluoro-3-methyl-indazol-1-yl)- 539.97 LC-MS 1FA propionyl]-1,2,3,4-tetrahydro- isoquinolin-1-yl}-phenoxy)-acetic acid 393 (4-Chloro-2-{(S)-6-fluoro-2-[3-(6- C28H24N3O4ClF2 1.10 540.3 fluoro-3-methyl-indazol-1-yl)- 539.97 LC-MS 1FA propionyl]-1,2,3,4-tetrahydro- isoquinolin-1-yl}-phenoxy)-acetic acid 394 (4-Chloro-2-{(S)-2-[3-(6-chloro-3- C28H24N3O4Cl2F 1.16 556.2 methyl-indazol-1-yl)-propionyl]-6- 556.42 LC-MS 1FA fluoro-1,2,3,4-tetrahydro- isoquinolin-1-yl}-phenoxy)-acetic acid 395 (4-Chloro-2-{(S)-6-fluoro-2-[3-(5- C27H22N3O4ClF2 1.07 526.3 fluoro-indazol-1-yl)-propionyl]- 525.94 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- yl}-phenoxy)-acetic acid 396 (4-Chloro-2-{(S)-2-[3-(5-chloro- C27H22N3O4Cl2F 1.13 542.2 indazol-1-yl)-propionyl]-6-fluoro- 542.39 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- yl}-phenoxy)-acetic acid 397 (4-Chloro-2-{(S)-6-fluoro-2-[3-(3- C28H25N3O4ClF 1.09 522.3 methyl-indazol-1-yl)propionyl]- 521.97 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- yl}-phenoxy)-acetic acid 398 (4-Chloro-2-{(S)-6-fluoro-2-[3-(6- C27H22N3O4ClF2 1.08 526.2 fluoro-indazol-1-yl)-propionyl]- 525.94 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- yl}-phenoxy)-acetic acid 399 (4-Chloro-2-{(S)-6-fluoro-2-[3-(4- C27H22N3O4ClF2 1.08 526.2 fluoro-indazol-1-yl)-propionyl]- 525.94 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- yl}-phenoxy)-acetic acid 400 (4-Chloro-2-{(S)-2-[3-(7-chloro- C27H22N3O4Cl2F 1.09 542.2 indazol-1-yl)-propionyl]-6-fluoro- 542.39 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- yl}-phenoxy)-acetic acid 401 (4-Chloro-2-{(S)-2-[3-(6-chloro- C27H22N3O4Cl2F 1.13 542.2 indazol-1-yl)-propionyl]-6-fluoro- 542.39 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- yl}-phenoxy)-acetic acid 402 (4-Chloro-2-{(S)-2-[3-(4-chloro- C27H22N3O4Cl2F 1.13 542.1 indazol-1-yl)-propionyl]-6-fluoro- 542.39 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- yl}-phenoxy)-acetic acid 403 (4-Chloro-2-{(S)-6-fluoro-2-[3-(7- C27H22N3O4ClF2 1.08 526.3 fluoro-indazol-1-yl)-propionyl]- 525.94 LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- yl}-phenoxy)-acetic acid 404 (±)-(4-Chloro-2-{2-[3-(3-chloro- C26H22N4O4Cl2 1.04 525.2 pyrrolo[2,3-b]pyrazin-5-yl)- 525.39 LC-MS 1FA propionyl]-1,2,3,4-tetrahydro- isoquinolin-1-yl}-phenoxy)-acetic acid 405 (±)-(4-Chloro-2-{2-[3-(2- C29H24N2O4ClF3 1.25 557.1 trifluoromethyl-indol-1-yl)- 556.97 LC-MS 1FA propionyl]-1,2,3,4-tetrahydro- isoquinolin-1-yl}-phenoxy)-acetic acid

Amide Coupling and Subsequent Saponification

Method A: To a solution of (2-methoxyphenoxy)acetic acid (22 mg, 0.12 mmol, 1.2 eq.) in DMF (0.3 mL), TBTU (39 mg, 0.12 mmol, 1.2 eq.) and Si-DEA (400 mg, 0.50 mmol, 5.0 eq.) were added. The resulting mixture was stirred at r.t. for 30 min. A solution of (±)-[4-chloro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (38 mg, 0.10 mmol, 1.0 eq.) in DCM/DMF 5:1 (0.6 mL) was added. The mixture was stirred at r.t. for 18 hours. The resulting suspension was filtered, the solids were rinsed with DCM (5 mL), and the filtrate was concentrated in vacuo. The residue was dissolved in THF (1 mL) and 1M aq. NaOH (1 mL) was added. The mixture was stirred at r.t. for 30 min. The mixture was acidified with 2M aq. HCl soln. and concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters X-Bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the desired acid as a white solid.

Listed in Table 22 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding amine of Structure 2 and the corresponding acid as starting materials.

TABLE 22 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 406 (±)-(4-Chloro-2-{2-[2-(2-methoxy- C26H24 1.28 482.1 phenoxy)-acetyl]-1,2,3,4- NO6Cl LC-MS 5 tetrahydro-isoquinolin-1-yl}- 481.93 phenoxy)-acetic acid 407 (±)-(4-Chloro-2-{2-[2-(4-fluoro- C25H21 1.07 470.2 phenoxy)-acetyl]-1,2,3,4- NO5ClF LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 469.90 phenoxy)-acetic acid 408 (±)-(4-Chloro-2-{2-[3-(6-methyl- C26H25 0.71 465.3 pyridin-2-yl)-propionyl]-1,2,3,4- N2O4Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 464.95 phenoxy)-acetic acid 409 (±)-{4-Chloro-2-[2-(2-phenoxy- C25H22 1.06 452.2 acetyl)-1,2,3,4-tetrahydro- N2O5Cl LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 451.91 acid 410 (±)-(4-Chloro-2-{2-[2-(2-fluoro- C25H21 1.07 470.2 phenoxy)-acetyl]-1,2,3,4- NO5ClF LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 469.90 phenoxy)-acetic acid 411 (±)-(4-Chloro-2-{2-[2-(quinolin-8- C28H23 0.80 503.3 yloxy)-acetyl]-1,2,3,4-tetrahydro- N2O5Cl LC-MS 1FA isoquinolin-1-yl}-phenoxy)-acetic 502.95 acid 412 (±)-(4-Chloro-2-{2-[2-(4-chloro- C25H21 1.12 486.2 phenoxy)-acetyl]-1,2,3,4- NO5Cl2 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 486.35 phenoxy)-acetic acid 413 (±)-(4-Chloro-2-{2-[2-(3-chloro- C25H21 1.12 486.2 phenoxy)-acetyl]-1,2,3,4- NO5Cl2 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 486.35 phenoxy)-acetic acid 414 (±)-{4-Chloro-2-[2-(2-p-tolyloxy- C26H24 1.11 466.2 acetyl)-1,2,3,4-tetrahydro- NO5Cl LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 465.93 acid 415 (±)-(4-Chloro-2-{2-[2-(4-methoxy- C26H24 1.05 482.2 phenoxy)-acetyl]-1,2,3,4- NO6Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 481.93 phenoxy)-acetic acid 416 (±)-(4-Chloro-2-{2-[2-(pyridin-3- C24H21 0.70 453.2 yloxy)-acetyl]-1,2,3,4-tetrahydro- N2O5Cl LC-MS 1FA isoquinolin-1-yl}-phenoxy)-acetic 452.89 acid 417 (±)-(4-Chloro-2-{2-[trans-2-(4- C28H26 1.10 492.3 methoxy-phenyl)- NO5Cl LC-MS 1FA cyclopropanecarbonyl]-1,2,3,4- 491.97 tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 418 (±)-(4-Chloro-2-{2-[trans-2-(4- C27H23 1.14 480.3 fluoro-phenyl)- NO4ClF LC-MS 1FA cyclopropanecarbonyl]-1,2,3,4- 479.93 tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 419 (±)-(4-Chloro-2-{2-[trans-2-(4- C28H23 1.20 530.2 trifluoromethyl-phenyl)- NO4ClF3 LC-MS 1FA cyclopropanecarbonyl]-1,2,3,4- 529.94 tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 420 (±)-{4-Chloro-2-[2-(trans-2-p-tolyl- C28H26 1.17 476.3 cyclopropanecarbonyl)-1,2,3,4- NO4Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl]- 475.97 phenoxy}-acetic acid 421 (±)-(4-Chloro-2-{2-[trans-2-(3- C27H23 1.17 496.1 chloro-phenyl)- NO4Cl2 LC-MS 1FA cyclopropanecarbonyl]-1,2,3,4- 496.39 tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 422 (±)-{4-Chloro-2-[2-(trans-2-o-tolyl- C28H26 1.15 476.3 cyclopropanecarbonyl)-1,2,3,4- NO4Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl]- 475.97 phenoxy}-acetic acid 423 (±)-(4-Chloro-2-{2-[trans-2-(2- C28H23 1.17 530.2 trifluoromethyl-phenyl)- NO4ClF3 LC-MS 1FA cyclopropanecarbonyl]-1,2,3,4- 529.94 tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 424 (±)-(4-Chloro-2-{2-[trans-2-(3- C27H23 1.12 480.2 fluoro-phenyl)- NO4ClF LC-MS 1FA cyclopropanecarbonyl]-1,2,3,4- 479.93 tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 425 (±)-(4-Chloro-2-{2-[trans-2-(3- C28H26 1.11 492.2 methoxy-phenyl)- NO5Cl LC-MS 1FA cyclopropanecarbonyl]-1,2,3,4- 491.97 tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 426 (±)-(4-Chloro-2-{2-[trans-2-(3- C28H23 1.19 530.3 trifluoromethyl-phenyl)- NO4ClF3 LC-MS 1FA cyclopropanecarbonyl]-1,2,3,4- 529.94 tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 427 (±)-{4-Chloro-2-[2-(trans-2-m-tolyl- C28H26 1.18 476.3 cyclopropanecarbonyl)-1,2,3,4- NO4Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl]- 475.97 phenoxy}-acetic acid 428 (±)-{4-Chloro-2-[6-fluoro-2-(trans- C27H23 1.12 480.2 2-phenyl-cyclopropanecarbonyl)- NO4ClF LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 479.93 yl]-phenoxy}-acetic acid 429 (±)-(4-Chloro-2-{6-fluoro-2-[trans- C28H22 1.17 548.2 2-(2-trifluoromethyl-phenyl)- NO4ClF4 LC-MS 1FA cyclopropanecarbonyl]-1,2,3,4- 547.93 tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 430 (±)-(4-Chloro-2-{2-[2-(trans-2- C27H22 1.16 514.2 chloro-phenyl)- NO4Cl2F LC-MS 1FA cyclopropanecarbonyl]-6-fluoro- 514.38 1,2,3,4-tetrahydro-isoquinolin-1- yl}-phenoxy)-acetic acid 431 (±)-{4-Chloro-2-[6-fluoro-2-(trans- C28H25 1.16 494.3 2-o-tolyl-cyclopropanecarbonyl)- NO4ClF LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 493.96 yl]-phenoxy}-acetic acid 432 (±)-(4-Chloro-2-{2-[2-(2,6- C26H24 0.73 499.3 dimethyl-pyridin-3-yloxy)-acetyl]-6- N2O5ClF LC-MS 1FA fluoro-1,2,3,4-tetrahydro- 498.94 isoquinolin-1-yl}-phenoxy)-acetic acid 433 (±)-(4-Chloro-2-{6-fluoro-2-[3-(5- C29H26 1.05 537.2 methoxy-1H-indol-3-yl)-propionyl]- N2O5ClF LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 536.99 yl}-phenoxy)-acetic acid 434 (±)-(4-Chloro-2-{6-fluoro-2-[3-(1- C29H26 1.15 521.3 methyl-1H-indol-3-yl)-propionyl]- N2O4ClF LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 520.99 yl}-phenoxy)-acetic acid 435 (±)-{4-Chloro-2-[6-fluoro-2-(3-o- C27H25 1.37 482.2 tolyl-propionyl)-1,2,3,4-tetrahydro- NO4ClF LC-MS 5 isoquinolin-1-yl]-phenoxy}-acetic 481.95 acid 436 (±)-(4-Chloro-2-{6-fluoro-2-[4-(2- C27H24 1.16 500.2 fluoro-phenyl)-butyryl]-1,2,3,4- NO4ClF2 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 499.94 phenoxy)-acetic acid 437 (±)-(4-Chloro-2-{2-[2-(2-chloro- C26H22 1.13 518.2 benzyloxy)-acetyl]-6-fluoro- NO5Cl2F LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 518.37 yl}-phenoxy)-acetic acid 438 (±)-(4-Chloro-2-{6-fluoro-2-[3-(4- C26H22 1.12 502.2 fluoro-phenoxy)-propionyl]-1,2,3,4- NO5ClF2 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 501.91 phenoxy)-acetic acid 439 (±)-(4-Chloro-2-{2-[2-(methyl- C26H25 1.09 465.3 phenyl-amino)-acetyl]-1,2,3,4- N2O4Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 464.95 phenoxy)-acetic acid 440 (±)-(4-Chloro-2-{2-[4-(2-oxo- C25H27 0.89 471.3 pyrrolidin-1-yl)-butyryl]-1,2,3,4- N2O5Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 470.95 phenoxy)-acetic acid 441 (±)-{4-Chloro-2-[2-(3-2,3-dihydro- C28H27 1.13 491.3 indol-1-yl-propionyl)-1,2,3,4- N2O4Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl]- 490.99 phenoxy}-acetic acid 442 (±)-(4-Chloro-2-{2-[3-(6-chloro-3- C28H24 1.10 555.0 oxo-2,3-dihydro-benzo[1,4]oxazin- N2O6Cl2 LC-MS 1FA 4-yl)-propionyl]-1,2,3,4-tetrahydro- 555.41 isoquinolin-1-yl}-phenoxy)-acetic acid 443 (±)-{4-Chloro-2-[2-(2-phenylamino- C25H23 1.06 451.3 acetyl)-1,2,3,4-tetrahydro- N2O4Cl LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 450.92 acid 444 (±)-{4-Chloro-2-[2-(2-1,3-dihydro- C27H25 0.83 477.2 isoindol-2-yl-acetyl)-1,2,3,4- N2O4Cl LC-MS tetrahydro-isoquinolin-1-yl]- 476.96 1TFA phenoxy}-acetic acid 445 (±)-(4-Chloro-2-{2-[3-(1-oxo-1,3- C28H25 0.96 505.3 dihydro-isoindol-2-yl)-propionyl]- N2O5Cl LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 504.97 yl}-phenoxy)-acetic acid 446 (±)-(4-Chloro-2-{2-[3-(2-methyl- C29H27 1.18 503.3 indol-1-yl)-propionyl]-1,2,3,4- N2O4Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 503.00 phenoxy)-acetic acid 447 (±)-(4-Chloro-2-{2-[3-(3-methyl- C29H27 1.20 503.3 indol-1-yl)-propionyl]-1,2,3,4- N2O4Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 503.00 phenoxy)-acetic acid 448 (±)-{4-Chloro-2-[2-(3-indazol-1-yl- C27H24 1.06 490.3 propionyl)-1,2,3,4-tetrahydro- N3O4Cl LC-MS isoquinolin-1-yl]-phenoxy}-acetic 489.96 1TFA acid 449 (±)-{4-Chloro-2-[2-(3-3,4-dihydro- C29H29 1.19 505.3 2H-quinolin-1-yl-propionyl)- N2O4Cl LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 505.01 yl]-phenoxy}-acetic acid 450 (±)-{4-Chloro-2-[2-(3-isobutoxy- C24H28 1.12 446.3 propionyl)-1,2,3,4-tetrahydro- NO5Cl LC-MS 1FA isoquinolin-1-yl]-phenoxy}-acetic 445.94 acid 451 (±)-{2-[2-(3-Benzoimidazol-1-yl- C27H24 0.80 490.2 propionyl)-1,2,3,4-tetrahydro- N3O4Cl LC-MS isoquinolin-1-yl]-4-chloro- 489.96 1TFA phenoxy}-acetic acid 452 (±)-(4-Chloro-2-{2-[3-(4-methyl-2- C24H23 0.97 487.2 oxo-thiazol-3-yl)-propionyl]- N2O5ClS LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 486.98 yl}-phenoxy)-acetic acid 453 (±)-(4-Chloro-2-{2-[3-(2-oxo- C23H23 0.92 475.2 thiazolidin-3-yl)-propionyl]-1,2,3,4- N2O5ClS LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 474.96 phenoxy)-acetic acid

Method B: To a solution of 3-(2,4-dimethylphenyl)propionic acid (18 mg, 0.10 mmol, 1.0 eq.) and (±)-[4-chloro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (41 mg, 0.10 mmol, 1.0 eq.) in DMF (1.2 mL), DMAP (49 mg, 0.40 mmol, 4.0 eq.) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (29 mg, 0.15 mmol, 1.5 eq.) were added. The resulting solution was stirred at r.t. for 18 hours. 1M aq. NaOH (0.6 mL) was added and the solution was stirred at r.t. during 2 hours. Formic acid (0.2 mL) was added. The crude mixture was purified by prep. HPLC (column: Atlantis, 19×50 mm, 5 um, UV/MS, acidic conditions) and evaporated (genevac) to give the desired acid.

Listed in Table 23 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding amine of Structure 2 and the corresponding acid as starting materials.

TABLE 23 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 454 (±)-(4-Chloro-2-{2-[3-(2,4- C28H28 1.21 478.3 dimethyl-phenyl)-propionyl]- NO4Cl LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 477.99 yl}-phenoxy)-acetic acid 455 (±)-(4-Chloro-2-{2-[3-(2,6- C27H27 0.69 479.3 dimethyl-pyridin-3-yl)-propionyl]- N2O4Cl LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 478.97 yl}-phenoxy)-acetic acid 456 (±)-(4-Chloro-2-{2-[2-(2,4- C27H26 1.18 480.3 dimethyl-phenoxy)-acetyl]-1,2,3,4- N2O5Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 479.96 phenoxy)-acetic acid 457 (±)-(4-Chloro-2-{2-[3-(1,2- C30H29 1.17 517.3 dimethyl-1H-indol-3-yl)-propionyl]- N2O4Cl LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 517.02 yl}-phenoxy)-acetic acid 458 (±)-(4-Chloro-2-{2-[3-(5-methoxy- C30H29 1.12 533.3 1-methyl-1H-indol-3-yl)-propionyl]- N2O5Cl LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 533.02 yl}-phenoxy)-acetic acid 459 (±)-(4-Chloro-2-{2-[3-(5-methoxy- C29H27 1.11 519.3 indol-1-yl)-propionyl]-1,2,3,4- N2O5Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 519.00 phenoxy)-acetic acid

Method C: To a solution of (±)-trans-2-ethyl-cyclopropanecarboxylic acid (35 mg, 0.31 mmol, 1.3 eq.) in DMF (2 mL), DIPEA (4 eq.) and TBTU (98 mg, 0.31 mmol, 1.3 eq.) were added in sequence. The resulting solution was stirred at r.t. for 30 min. ((S)-4-Chloro-2-1,2,3,4-tetrahydro-isoquinolin-1-yl-phenoxy)-acetic acid ethyl ester hydrochloride (90 mg, 0.24 mmol, 1.0 eq.) was added and the resulting mixture was stirred at r.t. for 18 hours. The solution was neutralized with formic acid (1 mL) and then purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo (Genevac). To a solution of the ethyl ester derivative in DMF (1 mL), 1M aq. NaOH (0.5 mL) was added. The mixture was stirred at r.t. for 18 hours. The solution was neutralized with formic acid (1 mL) and then purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo (Genevac) to give the desired acid.

Listed in Table 24 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding amine of Structure 2 and the corresponding acid as starting materials.

TABLE 24 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 460 {4-Chloro-2-[(S)-2-(trans-2-ethyl- C23H24 1.09 414.2 cyclopropanecarbonyl)-1,2,3,4- NO4Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl]- 413.90 phenoxy}-acetic acid 461 {4-Chloro-2-[(S)-2-(trans-2-ethoxy- C23H24 1.01 430.2 cyclopropanecarbonyl)-1,2,3,4- NO5Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl]- 429.90 phenoxy}-acetic acid 462 {4-Chloro-2-[(S)-2-(trans-2-methyl- C22H22 1.04 400.2 cyclopropanecarbonyl)-1,2,3,4- NO4Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl]- 399.87 phenoxy}-acetic acid 463 (±)-{4-Chloro-2-[2-(3-1H-indol-3-yl- C28H25 0.92 489.1 propionyl)-1,2,3,4-tetrahydro- N2O4Cl LC-MS 3 isoquinolin-1-yl]-phenoxy}-acetic 488.97 acid

Example 464 {4-Chloro-2-[(S)-2-(trans-2-isopropyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid (diastereoisomer 1) (C24H26NO4C1, MW=427.93) and Example 465 {4-Chloro-2-[(S)-2-(trans-2-isopropyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid (diastereoisomer 2) (C24H26NO4C1, MW=427.93)

To a solution of (±)-trans-2-isopropyl-cyclopropanecarboxylic acid (39 mg, 0.31 mmol, 1.3 eq.) in DMF (2 mL), DIPEA (4 eq.) and TBTU (98 mg, 0.31 mmol, 1.3 eq.) were added in sequence. The resulting solution was stirred at r.t. for 30 min. ((S)-4-Chloro-2-1,2,3,4-tetrahydro-isoquinolin-1-yl-phenoxy)-acetic acid ethyl ester hydrochloride (90 mg, 0.24 mmol, 1.0 eq.) was added and the resulting mixture was stirred at r.t. for 18 hours. The solution was neutralized with formic acid (1 mL) and then purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo (Genevac). To a solution of the ethyl ester derivative in DMF (1 mL), 1M aq. NaOH (0.5 mL) was added. The mixture was stirred at r.t. for 18 hours. The solution was neutralized with formic acid (1 mL) and then purified by prep. HPLC (column: Waters XBridge, 19×50 mm, 5 um, UV/MS, acidic conditions) and concentrated in vacuo (Genevac) to give {4-Chloro-2-[(S)-2-(trans-2-isopropyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid (diastereoisomer 1) (LC-MS 1FA: t_(R)=1.13 min; [M+H]⁺=428.3) and {4-Chloro-2-[(S)-2-(trans-2-isopropyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid (diastereoisomer 2) (LC-MS 1FA: t_(R)=1.15 min; [M+H]⁺=428.3)

Example 466 (±)-{4-Chloro-2-[2-(2,2-dimethyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid (C23H24NO4C1, MW=413.90)

To a solution of (±)-2,2-dimethyl-cyclopropanecarboxylic acid (26 mg, 0.20 mmol, 1.0 eq.) and (±)-[4-chloro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester (73 mg, 0.20 mmol, 1.0 eq.) in DMF (2.4 mL), DMAP (37 mg, 0.30 mmol, 1.5 eq.) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (58 mg, 0.30 mmol, 1.5 eq.) were added. The resulting solution was stirred at r.t. for 62 hours. 1M aq. NaOH soln. (1.2 mL) was added and the solution was stirred at r.t. for 3.5 hours. Formic acid (0.2 mL) was added. The crude mixture was purified by prep. HPLC (column: Waters XBridge, 19×50 mm, 5 um, UV/MS, acidic conditions). The two racemic diastereoisomers were separated (LC-MS 3: t_(R) (±)-dial=0.91 and t_(R) (±)-dia2=0.93). The title compound showed: t_(R)=0.93.

LC-MS 1FA: t_(R)=1.09 min; [M+H]⁺=414.3

Example 467 (±)-(4-Chloro-2-{2-[2-(2,4-dimethyl-thiazol-5-yl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid (C26H25N2O4ClS, MW=497.01)

To a solution of (±)-trans-2-(2,4-dimethyl-thiazol-5-yl)cyclopropanecarboxylic acid (42 mg, 0.20 mmol, 1.0 eq.) and (±)-[4-chloro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester (73 mg, 0.20 mmol, 1.0 eq.) in DMF (2.4 mL), DMAP (37 mg, 0.30 mmol, 1.5 eq.) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (58 mg, 0.30 mmol, 1.5 eq.) were added. The resulting solution was stirred at r.t. for 62 hours. 1M aq. NaOH soln. (1.2 mL) was added and the solution was stirred at r.t. for 3.5 hours. Formic acid (0.2 mL) was added. The crude mixture was purified by prep. HPLC (column: Waters XBridge, 19×50 mm, 5 um, UV/MS, acidic conditions). The two racemic diastereoisomers were separated (LC-MS 3: t_(R) (±)-dial=0.81 and t_(R) (±)-dia2=0.82). The title compound showed: t_(R)=0.82.

LC-MS 1 FA: t_(R)=0.99 min; [M+H]⁺=497.3

Alcohol Alkylation and Subsequent Saponification

Method A: To a mixture of 3-hydroxy-6-methylpyridine (13 mg, 0.12 mmol, 1.2 eq.) and potassium carbonate (22 mg, 0.16 mmol, 1.6 eq.) in MeCN (0.8 mL) at 75° C., a solution of (±)-{2-[2-(2-bromo-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-chloro-phenoxy}-acetic acid ethyl ester (47 mg, 0.10 mmol, 1.0 eq.) in MeCN (0.2 mL) was added. The reaction mixture was stirred at 75° C. for 2 hours and further at r.t. for 18 hours. 1M aq. NaOH soln. (1 mL) was added and the mixture was stirred at r.t. for 1 hour. The mixture was acidified with 2M aq. HCl soln. and purified by prep. HPLC (column: Waters X-Bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the desired acid as a white solid.

Listed in Table 25 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding alcohol as starting material.

TABLE 25 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 468 (±)-(4-Chloro-2-{2-[2-(6-methyl- C25H23 0.74 467.3 pyridin-3-yloxy)-acetyl]-1,2,3,4- N2O5Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 466.92 phenoxy)-acetic acid 469 (±)-(4-Chloro-2-{2-[2-(2-methyl- C25H23 0.72 467.3 pyridin-3-yloxy)-acetyl]-1,2,3,4- N2O5Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 466.92 phenoxy)-acetic acid 470 (±)-(4-Chloro-2-{2-[2-(5-chloro- C24H20 1.00 487.2 pyridin-3-yloxy)-acetyl]-1,2,3,4- N2O5Cl2 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 487.34 phenoxy)-acetic acid 471 (±)-(4-Chloro-2-{2-[2-(2-chloro- C24H20 0.99 487.2 pyridin-3-yloxy)-acetyl]-1,2,3,4- N2O5Cl2 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 487.34 phenoxy)-acetic acid 472 (±)-(4-Chloro-2-{2-[2-(6-chloro- C24H20 1.01 487.2 pyridin-3-yloxy)-acetyl]-1,2,3,4- N2O5Cl2 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 487.34 phenoxy)-acetic acid 473 (±)-(4-Chloro-2-{2-[2-(2,6-dichloro- C24H19 1.09 521.1 pyridin-4-yloxy)-acetyl]-1,2,3,4- N2O5Cl3 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 521.78 phenoxy)-acetic acid

Method B: To a solution of 3-hydroxy-5-methylpyridine (12 mg, 0.10 mmol, 1.0 eq.) in DMF (1.0 mL), 60% sodium hydride in mineral oil (4.4 mg, 0.11 mmol, 1.1 eq.) was added. The mixture was stirred at r.t. for 10 min. A solution of (±)-{2-[2-(2-bromo-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-chloro-phenoxy}-acetic acid ethyl ester (47 mg, 0.10 mmol, 1.0 eq.) in DMF (0.3 mL) was added and the reaction mixture was stirred at r.t. for 4 hours. 1M aq. NaOH soln. (1.0 mL) was added. The solution was stirred at r.t. for 30 min. The reaction mixture was acidified with 2M aq. HCl soln. (1.0 mL) and concentrated in vacuo. The residue, redissolved in DMF (1.2 mL), was purified by prep. HPLC (column: Atlantis, 19×50 mm, 5 um, UV/MS, acidic conditions) to give the desired acid.

Listed in Table 26 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding alcohol as starting material.

TABLE 26 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 474 (±)-(4-Chloro-2-{2-[2-(5-methyl- C25H23 0.78 467.3 pyridin-3-yloxy)-acetyl]-1,2,3,4- N2O5Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 466.92 phenoxy)-acetic acid 475 (±)-[4-Chloro-2-(2-{2-[2-(2- C26H25 0.90 513.2 hydroxy-ethoxy)-pyridin-3-yloxy]- N2O7Cl LC-MS 1FA acetyl}-1,2,3,4-tetrahydro- 512.95 isoquinolin-1-yl)-phenoxy]-acetic acid 476 (±)-(4-Chloro-2-{2-[2-(2,6- C26H25 1.07 513.2 dimethoxy-pyridin-3-yloxy)-acetyl]- N2O7Cl LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 512.95 yl}-phenoxy)-acetic acid 477 (±)-(4-Chloro-2-{2-[2-(5-methoxy- C25H23 0.87 483.3 pyridin-3-yloxy)-acetyl]-1,2,3,4- N2O6Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 482.92 phenoxy)-acetic acid 478 (±)-(4-Chloro-2-{2-[2-(5-fluoro- C24H20 0.95 471.2 pyridin-3-yloxy)-acetyl]-1,2,3,4- N2O5ClF LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 470.88 phenoxy)-acetic acid 479 (±)-(2-{2-[2-(2-Carbamoyl-pyridin- C25H22 0.82 496.2 3-yloxy)-acetyl]-1,2,3,4-tetrahydro- N3O6Cl LC-MS 1FA isoquinolin-1-yl}-4-chloro- 495.92 phenoxy)-acetic acid 480 (±)-(4-Chloro-2-{2-[2-(2-cyano- C25H20 0.95 478.2 pyridin-3-yloxy)-acetyl]-1,2,3,4- N3O5Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 477.90 phenoxy)-acetic acid 481 (±)-(4-Chloro-2-{2-[2-(6- C25H20 1.06 521.2 trifluoromethyl-pyridin-3-yloxy)- N2O5ClF3 LC-MS 1FA acetyl]-1,2,3,4-tetrahydro- 520.89 isoquinolin-1-yl}-phenoxy)-acetic acid 482 (±)-(4-Chloro-2-{2-[2-(2-fluoro- C24H20 0.97 471.2 pyridin-3-yloxy)-acetyl]-1,2,3,4- N2O5ClF LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 470.88 phenoxy)-acetic acid 483 (±)-(4-Chloro-2-{2-[2-(3-methyl- C26H23 0.90 507.2 3H-imidazo[4,5-b]pyridin-6-yloxy)- N4O5Cl LC-MS 5 acetyl]-1,2,3,4-tetrahydro- 506.95 isoquinolin-1-yl}-phenoxy)-acetic acid 484 (±)-(4-Chloro-2-{2-[2-(2-methoxy- C26H25 1.02 497.3 5-methyl-pyridin-3-yloxy)-acetyl]- N2O6Cl LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 496.95 yl}-phenoxy)-acetic acid 485 (±)-(4-Chloro-2-{2-[2-(5,6- C26H25 0.98 513.3 dimethoxy-pyridin-3-yloxy)-acetyl]- N2O7Cl LC-MS 1FA 1,2,3,4-tetrahydro-isoquinolin-1- 512.95 yl}-phenoxy)-acetic acid 486 (±)-(4-Chloro-2-{2-[2-(6-methoxy- C25H23 0.99 483.3 pyridin-3-yloxy)-acetyl]-1,2,3,4- N2O6Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 482.92 phenoxy)-acetic acid 487 (±)-(4-Chloro-2-{2-[2-(4-chloro- C24H20 0.97 487.2 pyridin-3-yloxy)-acetyl]-1,2,3,4- N2O5Cl2 LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 487.34 phenoxy)-acetic acid

Alkylation and Subsequent Saponification

To a solution of (±)-{2-[2-(2-bromo-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-chloro-phenoxy}-acetic acid ethyl ester (47 mg, 0.10 mmol, 1.0 eq.) and cesium carbonate (65 mg, 0.20 mmol, 2.0 eq.) in DMF (0.8 mL), 3-methylindole (13 mg, 0.10 mmol, 1.0 eq.) was added. The mixture was stirred at 80° C. for 17 hours. The mixture was allowed to cool to r.t. 1M aq. NaOH soln. (0.2 mL) was added. The mixture was stirred at r.t. for 4 hours. The mixture was neutralized with formic acid (ca. 0.2 mL) and purified by prep. HPLC (column: Water X-Bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo (Genevac) to give the desired acid.

Listed in Table 27 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding indole as starting material.

TABLE 27 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 488 (±)-(4-Chloro-2-{2-[2-(3-methyl- C28H25 1.15 489.3 indol-1-yl)-acetyl]-1,2,3,4- N2O4Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 488.97 phenoxy)-acetic acid 489 (±)-(4-Chloro-2-{2-[2-(5-methoxy- C28H25 1.07 505.2 indol-1-yl)-acetyl]-1,2,3,4- N2O5Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl}- 504.97 phenoxy)-acetic acid

Urea Formation and Subsequent Saponification

To a solution of (±)-[4-chloro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (50 mg, 0.13 mmol, 1.00 eq.) and NEt₃ (55 μL, 0.39 mmol, 3.00 eq.) in MeCN (1 mL), 2-chlorobenzyl isocyanate (23 mg, 0.14 mmol, 1.05 eq.) in MeCN (1 mL) was added. The mixture was stirred at r.t. for 18 hours. 1M aq. NaOH (0.5 mL) was added. The mixture was stirred at r.t. for 18 hours. The solution was neutralized with formic acid and purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo (Genevac) to give the desired acid.

Listed in Table 28 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding amine of Structure 2 and the corresponding isocyanate as starting materials.

TABLE 28 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 490 (±)-{4-Chloro-2-[2-(2-chloro- C25H22 1.08 485.2 benzylcarbamoyl)-1,2,3,4- N2O4Cl2 LC-MS 1FA tetrahydro-isoquinolin-1-yl]- 485.37 phenoxy}-acetic acid 491 (±)-{4-Chloro-2-[2-(3-fluoro- C25H22 1.05 469.2 benzylcarbamoyl)-1,2,3,4- N2O4ClF LC-MS 1FA tetrahydro-isoquinolin-1-yl]- 468.91 phenoxy}-acetic acid 492 (±)-[2-(2-Benzylcarbamoyl-1,2,3,4- C25H23 1.04 451.2 tetrahydro-isoquinolin-1-yl)-4- N2O4Cl LC-MS 1FA chloro-phenoxy]-acetic acid 450.92 493 (±)-[4-Chloro-2-(2- C26H25 1.08 465.3 phenethylcarbamoyl-1,2,3,4- N2O4Cl LC-MS 1FA tetrahydro-isoquinolin-1-yl)- 464.95 phenoxy]-acetic acid 494 (±)-{4-Chloro-2-[2-(4-fluoro- C25H22 1.05 469.2 benzylcarbamoyl)-1,2,3,4- N2O4ClF LC-MS 1FA tetrahydro-isoquinolin-1-yl]- 468.91 phenoxy}-acetic acid 495 (±)-{4-Chloro-2-[2-(2-fluoro- C25H22 1.05 469.2 benzylcarbamoyl)-1,2,3,4- N2O4ClF LC-MS 1FA tetrahydro-isoquinolin-1-yl]- 468.91 phenoxy}-acetic acid 496 (±)-[2-(2-Butylcarbamoyl-1,2,3,4- C22H25 1.04 417.3 tetrahydro-isoquinolin-1-yl)-4- N2O4Cl LC-MS 1FA chloro-phenoxy]-acetic acid 416.90

Suzuki Cross-Coupling and Subsequent Saponification

To a mixture under N2 of (±)-7-bromo-1-(2-ethoxycarbonylmethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (113 mg, 0.20 mmol, 1.00 eq.), 4-fluorobenzeneboronic acid (29 mg, 0.20 mmol, 1.00 eq.) and sodium carbonate (85 mg, 0.80 mmol, 4.00 eq.) in toluene/MeOH/water 20:4:1 (4 mL), tetrakis(triphenylphosphine) palladium (0) (12 mg, 0.01 mmol, 0.05 eq.) was added and the mixture was stirred at 100° C. in a sealed vial for 18 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. To a solution of the residue in DMF (0.9 mL), 1M aq. NaOH solution (0.25 mL) was added. The solution was stirred at r.t. for 18 hours, then acidified with formic acid (0.25 mL). The crude mixture was filtered over celite and purified by prep. HPLC (column: Atlantis, 19×50 mm, 5 um, UV/MS, acidic conditions) and evaporated (genevac) to give the desired acid.

Listed in Table 29 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding boronic acid as starting material.

TABLE 29 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 497 (±)-1-(2-Carboxymethoxy-5-fluoro- C31H25 1.24 530.3 phenyl)-7-(4-fluoro-phenyl)-3,4- NO5F2 LC-MS 1FA dihydro-1H-isoquinoline-2- 529.54 carboxylic acid benzyl ester 498 (±)-1-(2-Carboxymethoxy-5-fluoro- C29H24 1.00 514.3 phenyl)-7-pyrimidin-5-yl-3,4- N3O5F LC-MS 1FA dihydro-1H-isoquinoline-2- 513.52 carboxylic acid benzyl ester

Phenol Alkylation and Subsequent Saponification

To a suspension of (±)-1-(5-fluoro-2-hydroxy-phenyl)-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester (14 mg, 0.038 mmol, 1.0 eq.) and cesium carbonate (37 mg, 0.115 mmol, 3.0 eq.) in DMF (1 mL), ethyl bromoacetate (6 μL, 0.057 mmol, 1.5 eq.) was added. The reaction mixture was stirred at r.t. for 18 hours. The reaction mixture was diluted with water (25 mL) and AcOEt (30 mL). The layers were separated. The aq. phase was extracted with AcOEt (2×15 mL). The comb. org. phases were washed with water (1×10 mL), sat. aq. NaCl soln. (1×10 mL), dried over MgSO₄, and concentrated in vacuo. The residue was dissolved in DMF (1 mL), 1M aq. NaOH (1 mL) was added. The resulting solution was stirred at r.t. for 18 hours. The solution was neutralized with formic acid (1.00 mL), filtered and then purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid.

Listed in Table 30 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding phenol 30 as starting material.

TABLE 30 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 499 (±)-1-(2-Carboxymethoxy-5-fluoro- C24H20 0.89 422.0 phenyl)-1,3-dihydro-isoindole-2- NO5F LC-MS 3 carboxylic acid benzyl ester 421.42 500 (±)-1-(2-Carboxymethoxy-5- C24H19 1.10 456.2 chloro-phenyl)-5-fluoro-1,3- NO5ClF LC-MS 1FA dihydro-isoindole-2-carboxylic acid 455.87 benzyl ester 501 (±)-1-(2-Carboxymethoxy-5- C24H19 1.12 456.2 chloro-phenyl)-4-fluoro-1,3- NO5ClF LC-MS 1FA dihydro-isoindole-2-carboxylic acid 455.87 benzyl ester

Amide Coupling and Subsequent Saponification

To a solution of (2-methoxyphenoxy)acetic acid (22 mg, 0.12 mmol, 1.2 eq.) in DMF (1 mL), TBTU (39 mg, 0.12 mmol, 1.2 eq.) and DIPEA (51 μL, 0.30 mmol, 3.0 eq.) were added. The resulting mixture was stirred at r.t. for 30 min. A solution of (±)-[4-chloro-2-(2,3-dihydro-1H-isoindol-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (37 mg, 0.10 mmol, 1.0 eq.) in DMF (0.5 mL) was added. The mixture was stirred at r.t. for 1 hour. 1M aq. NaOH (1 mL) was added and the mixture was stirred at r.t. for 30 min, then concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters X-Bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the desired acid as a white solid.

Listed in Table 31 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding amine of Structure 2 and the corresponding acid as starting materials.

TABLE 31 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 502 (±)-(4-Chloro-2-{2-[2-(2-methoxy- C25H22 0.97 468.2 phenoxy)-acetyl]-2,3-dihydro-1H- NO6Cl LC-MS 1FA isoindol-1-yl}-phenoxy)-acetic acid 467.90 503 {4-Chloro-2-[2-trans-(2-phenyl- C26H22 1.03 448.2 cyclopropanecarbonyl)-2,3- NO4Cl LC-MS 1FA dihydro-1H-isoindol-1-yl]- 447.92 phenoxy}-acetic acid 504 (±)-(4-Chloro-2-{2-[2-(4-fluoro- C24H19 1.00 456.2 phenoxy)-acetyl]-2,3-dihydro-1H- NO5ClF LC-MS 1FA isoindol-1-yl}-phenoxy)-acetic acid 455.87 505 (±)-{4-Chloro-2-[2-(3-pyridin-3-yl- C24H21 0.65 437.3 propionyl)-2,3-dihydro-1H- N2O4Cl LC-MS 1FA isoindol-1-yl]-phenoxy}-acetic acid 436.89 506 (±)-{4-Chloro-2-[2-(3-o-tolyl- C26H24 1.08 450.2 propionyl)-2,3-dihydro-1H- NO4Cl LC-MS 1FA isoindol-1-yl]-phenoxy}-acetic acid 449.93 507 (±)-{4-Chloro-2-[2-(2-indol-1-yl- C26H21 1.28 461.2 acetyl)-2,3-dihydro-1H-isoindol-1- N2O4Cl LC-MS 5 yl]-phenoxy}-acetic acid 460.92 508 (±)-(4-Chloro-2-{2-[3-(1-ethyl-2- C30H29 1.13 517.3 methyl-1H-indol-3-yl)-propionyl]- N2O4Cl LC-MS 1FA 2,3-dihydro-1H-isoindol-1-yl}- 517.02 phenoxy)-acetic acid 509 (±)-(4-Chloro-2-{2-[2-(quinolin-8- C27H21 0.75 489.2 yloxy)-acetyl]-2,3-dihydro-1H- N2O5Cl LC-MS 1FA isoindol-1-yl}-phenoxy)-acetic acid 488.93 510 (±)-(4-Chloro-2-{2-[3-(2-methyl- C28H25 1.01 489.3 1H-indol-3-yl)-propionyl]-2,3- N2O4Cl LC-MS 1FA dihydro-1H-isoindol-1-yl}- 488.97 phenoxy)-acetic acid 511 (±)-(4-Chloro-2-{2-[3-(5-methoxy- C28H25 0.96 505.3 1H-indol-3-yl)-propionyl]-2,3- N2O5Cl LC-MS 1FA dihydro-1H-isoindol-1-yl}- 504.97 phenoxy)-acetic acid 512 (±)-(4-Chloro-2-{2-[2-(2,6- C25H23 0.66 467.3 dimethyl-pyridin-3-yloxy)-acetyl]- N2O5Cl LC-MS 1FA 2,3-dihydro-1H-isoindol-1-yl}- 466.92 phenoxy)-acetic acid 513 (±)-(4-Chloro-2-{2-[3-(1-methyl- C28H25 1.07 489.2 1H-indol-3-yl)-propionyl]-2,3- N2O4Cl LC-MS 1FA dihydro-1H-isoindol-1-yl}- 488.97 phenoxy)-acetic acid 514 (±)-{4-Chloro-2-[2-(3-2,3-dihydro- C27H25 1.05 477.3 indol-1-yl-propionyl)-2,3-dihydro- N2O4Cl LC-MS 1FA 1H-isoindol-1-yl]-phenoxy}-acetic 476.96 acid 515 (±)-{4-Chloro-2-[2-(3-3,4-dihydro- C28H27 1.10 491.3 2H-quinolin-1-yl-propionyl)-2,3- N2O4Cl LC-MS 1FA dihydro-1H-isoindol-1-yl]- 490.99 phenoxy}-acetic acid 516 (±)-{4-Chloro-2-[2-(3-indazol-1-yl- C26H22 0.99 476.3 propionyl)-2,3-dihydro-1H- N3O4Cl LC-MS 1FA isoindol-1-yl]-phenoxy}-acetic acid 475.93 517 (±)-(4-Chloro-2-{2-[3-(3-fluoro- C25H21 1.30 469.8 phenoxy)-propionyl]-2,3-dihydro- NO5ClF LC-MS 5 1H-isoindol-1-yl}-phenoxy)-acetic 469.90 acid 518 (±)-(4-Chloro-2-{2-[2-(5-methoxy- C26H21 0.99 493.2 benzo[d]isoxazol-3-yl)-acetyl]-2,3- N2O6Cl LC-MS 1FA dihydro-1H-isoindol-1-yl}- 492.91 phenoxy)-acetic acid 519 (±)-(4-Chloro-2-{2-[3-(3-methyl- C28H25 1.12 489.3 indol-1-yl)-propionyl]-2,3-dihydro- N2O4Cl LC-MS 1FA 1H-isoindol-1-yl}-phenoxy)-acetic 488.97 acid 520 (±)-(4-Chloro-2-{2-[3-(4-fluoro- C25H21 1.29 469.8 phenoxy)-propionyl]-2,3-dihydro- NO5ClF LC-MS 5 1H-isoindol-1-yl}-phenoxy)-acetic 469.90 acid 521 (±)-(4-Chloro-2-{2-[2-(2-chloro- C25H21 1.06 486.2 benzyloxy)-acetyl]-2,3-dihydro-1H- N2O5Cl2 LC-MS 1FA isoindol-1-yl}-phenoxy)-acetic acid 486.35 522 (±)-(4-Chloro-2-{2-[3-(2-fluoro- C25H21 1.03 470.2 phenoxy)-propionyl]-2,3-dihydro- NO5ClF LC-MS 1FA 1H-isoindol-1-yl}-phenoxy)-acetic 469.90 acid 523 (4-Chloro-2-{2-trans-[2-(3-fluoro- C26H21 1.03 466.2 phenyl)-cyclopropanecarbonyl]- NO4ClF LC-MS 1FA 2,3-dihydro-1H-isoindol-1-yl}- 465.91 phenoxy)-acetic acid 524 (4-Chloro-2-{2-trans-[2-(3-chloro- C26H21 1.08 482.1 phenyl)-cyclopropanecarbonyl]- NO4Cl2 LC-MS 1FA 2,3-dihydro-1H-isoindol-1-yl}- 482.36 phenoxy)-acetic acid 525 (4-Chloro-2-{2-trans-[2-(2-fluoro- C26H21 1.03 466.2 phenyl)-cyclopropanecarbonyl]- NO4ClF LC-MS 1FA 2,3-dihydro-1H-isoindol-1-yl}- 465.91 phenoxy)-acetic acid

Example 526 (±)-{4-Chloro-2-[5-fluoro-2-(3-indazol-1-yl-propionyl)-2,3-dihydro-1H-isoindol-1-yl]-phenoxy}-acetic acid (C26H21N3O4ClF, MW=493.92)

To a solution of 3-indazol-1-yl-propionic acid (34 mg, 0.17 mmol, 1.2 eq.) in DMF (4 mL), DIPEA (0.12 mL, 0.70 mmol, 5.0 eq.) and TBTU (54 mg, 0.17 mmol, 1.2 eq.) were added in sequence. The resulting solution was stirred at r.t. for 30 min. (±)-[4-Chloro-2-(5-fluoro-2,3-dihydro-1H-isoindol-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (60 mg, 0.14 mmol, 1.0 eq.) in DMF (1 mL) was added and the resulting mixture was stirred at r.t. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo. The resulting ester derivative was dissolved in DMF (0.50 mL) and 1M aq. NaOH (0.50 mL) was added. The resulting solution was stirred at r.t. for 18 hours. The solution was acidified with formic acid (1.0 mL), filtered, and then purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid.

LC-MS 1 FA: t_(R)=1.00 min; [M+H]⁺=494.2

Michael Addition

Potassium fluoride 40 wt. % on alumina (218 mg, 3.75 mmol, 25 eq.) was added to a mixture of [2-((S)-2-acryloyl-2,3-dihydro-1H-isoindol-1-yl)-4-chloro-phenoxy]-acetic acid ethyl ester (58 mg, 0.15 mmol, 1.0 eq.) and 5-fluoro-1H-indazole (25 mg, 0.18 mmol, 1.2 eq.) in MeCN (1 mL). The resulting suspension was stirred at 80° C. for 18 hours. Formic acid was added (0.2 mL). The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired product as a white foam.

Listed in Table 32 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding vinyl amide 8 and the corresponding heterocycle 9 as starting materials.

TABLE 32 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 527 (4-Chloro-2-{2-[3-(5-fluoro-indazol- C26H21 1.00 494.2 1-yl)-propionyl]-2,3-dihydro-1H- N3O4ClF LC-MS 1FA isoindol-1-yl}-phenoxy)-acetic acid 493.92 (enantiomer 1) 528 (4-Chloro-2-{2-[3-(4-fluoro-3- C27H23 1.05 508.3 methyl-indazol-1-yl)-propionyl]- N3O4ClF LC-MS 1FA 2,3-dihydro-1H-isoindol-1-yl}- 507.95 phenoxy)-acetic acid (enantiomer 1) 529 (4-Chloro-2-{2-[3-(4-chloro-3- C27H23 1.11 524.2 methyl-indazol-1-yl)-propionyl]- N3O4Cl2 LC-MS 1FA 2,3-dihydro-1H-isoindol-1-yl}- 524.40 phenoxy)-acetic acid (enantiomer 1) 530 (4-Chloro-2-{2-[3-(7-fluoro-3- C27H23 1.04 508.2 methyl-indazol-1-yl)-propionyl]- N3O4ClF LC-MS 1FA 2,3-dihydro-1H-isoindol-1-yl}- 507.95 phenoxy)-acetic acid (enantiomer 1) 531 (4-Chloro-2-{2-[3-(6-fluoro-3- C27H23 1.03 508.2 methyl-indazol-1-yl)-propionyl]- N3O4ClF LC-MS 1FA 2,3-dihydro-1H-isoindol-1-yl}- 507.95 phenoxy)-acetic acid (enantiomer 1) 532 (4-Chloro-2-{2-[3-(6-chloro-3- C27H23 1.09 524.2 methyl-indazol-1-yl)-propionyl]- N3O4Cl2 LC-MS 1FA 2,3-dihydro-1H-isoindol-1-yl}- 524.40 phenoxy)-acetic acid (enantiomer 1) 533 (4-Chloro-2-{2-[3-(3-methyl- C27H24 1.02 490.3 indazol-1-yl)-propionyl]-2,3- N3O4Cl LC-MS 1FA dihydro-1H-isoindol-1-yl}- 489.96 phenoxy)-acetic acid (enantiomer 1) 534 (4-Chloro-2-{2-[3-(6-fluoro-indazol- C26H21 1.00 494.2 1-yl)-propionyl]-2,3-dihydro-1H- N3O4ClF LC-MS 1FA isoindol-1-yl}-phenoxy)-acetic acid 493.92 (enantiomer 1) 535 (4-Chloro-2-{2-[3-(4-fluoro-indazol- C26H21 1.02 494.3 1-yl)-propionyl]-2,3-dihydro-1H- N3O4ClF LC-MS 1FA isoindol-1-yl}-phenoxy)-acetic acid 493.92 (enantiomer 1) 536 (4-Chloro-2-{2-[3-(7-chloro- C26H21 1.02 510.2 indazol-1-yl)-propionyl]-2,3- N3O4Cl2 LC-MS 1FA dihydro-1H-isoindol-1-yl}- 510.38 phenoxy)-acetic acid (enantiomer 1) 537 (4-Chloro-2-{2-[3-(7-fluoro-indazol- C26H21 1.01 494.2 1-yl)-propionyl]-2,3-dihydro-1H- N3O4ClF LC-MS 1FA isoindol-1-yl}-phenoxy)-acetic acid 493.92 (enantiomer 1) 538 (4-Chloro-2-{2-[3-(4-fluoro-3- C27H23 1.05 508.3 methyl-indazol-1-yl)-propionyl]- N3O4ClF LC-MS 1FA 2,3-dihydro-1H-isoindol-1-yl}- 507.95 phenoxy)-acetic acid (enantiomer 2) 539 (4-Chloro-2-{2-[3-(4-chloro-3- C27H23 1.11 524.2 methyl-indazol-1-yl)-propionyl]- N3O4Cl2 LC-MS 1FA 2,3-dihydro-1H-isoindol-1-yl}- 524.40 phenoxy)-acetic acid (enantiomer 2) 540 (4-Chloro-2-{2-[3-(7-fluoro-3- C27H23 1.04 508.2 methyl-indazol-1-yl)-propionyl]- N3O4ClF LC-MS 1FA 2,3-dihydro-1H-isoindol-1-yl}- 507.95 phenoxy)-acetic acid (enantiomer 2) 541 (4-Chloro-2-{2-[3-(6-fluoro-3- C27H23 1.03 508.2 methyl-indazol-1-yl)-propionyl]- N3O4ClF LC-MS 1FA 2,3-dihydro-1H-isoindol-1-yl}- 507.95 phenoxy)-acetic acid (enantiomer 2) 542 (4-Chloro-2-{2-[3-(6-chloro-3- C27H23 1.09 524.2 methyl-indazol-1-yl)-propionyl]- N3O4Cl2 LC-MS 1FA 2,3-dihydro-1H-isoindol-1-yl}- 524.40 phenoxy)-acetic acid (enantiomer 2) 543 (4-Chloro-2-{2-[3-(5-fluoro-indazol- C26H21 1.00 494.2 1-yl)-propionyl]-2,3-dihydro-1H- N3O4ClF LC-MS 1FA isoindol-1-yl}-phenoxy)-acetic acid 493.92 (enantiomer 2) 544 (4-Chloro-2-{2-[3-(5-chloro- C26H21 1.06 510.2 indazol-1-yl)-propionyl]-2,3- N3O4Cl2 LC-MS 1FA dihydro-1H-isoindol-1-yl}- 510.38 phenoxy)-acetic acid (enantiomer 2) 545 (4-Chloro-2-{2-[3-(3-methyl- C27H24 1.02 490.3 indazol-1-yl)-propionyl]-2,3- N3O4Cl LC-MS 1FA dihydro-1H-isoindol-1-yl}- 489.96 phenoxy)-acetic acid (enantiomer 2) 546 (4-Chloro-2-{2-[3-(6-fluoro-indazol- C26H21 1.00 494.2 1-yl)-propionyl]-2,3-dihydro-1H- N3O4ClF LC-MS 1FA isoindol-1-yl}-phenoxy)-acetic acid 493.92 (enantiomer 2) 547 (4-Chloro-2-{2-[3-(4-fluoro-indazol- C26H21 1.02 494.2 1-yl)-propionyl]-2,3-dihydro-1H- N3O4ClF LC-MS 1FA isoindol-1-yl}-phenoxy)-acetic acid 493.92 (enantiomer 2) 548 (4-Chloro-2-{2-[3-(7-chloro- C26H21 1.02 510.2 indazol-1-yl)-propionyl]-2,3- N3O4Cl2 LC-MS 1FA dihydro-1H-isoindol-1-yl}- 510.38 phenoxy)-acetic acid (enantiomer 2) 549 (4-Chloro-2-{2-[3-(6-chloro- C26H21 1.06 510.2 indazol-1-yl)-propionyl]-2,3- N3O4Cl2 LC-MS 1FA dihydro-1H-isoindol-1-yl}- 510.38 phenoxy)-acetic acid (enantiomer 2) 550 (4-Chloro-2-{2-[3-(4-chloro- C26H21 1.07 510.2 indazol-1-yl)-propionyl]-2,3- N3O4Cl2 LC-MS 1FA dihydro-1H-isoindol-1-yl}- 510.38 phenoxy)-acetic acid (enantiomer 2) 551 (4-Chloro-2-{2-[3-(7-fluoro-indazol- C26H21 1.01 494.2 1-yl)-propionyl]-2,3-dihydro-1H- N3O4ClF LC-MS 1FA isoindol-1-yl}-phenoxy)-acetic acid 493.92 (enantiomer 2)

Urea Formation and Subsequent Saponification

To a solution of (±)-[4-chloro-2-(2,3-dihydro-1H-isoindol-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (40 mg, 0.11 mmol, 1.00 eq.) and NEt₃ (45 μL, 0.33 mmol, 3.00 eq.) in MeCN (1 mL), a solution of 2-fluorobenzyl isocyanate (17 mg, 0.11 mmol, 1.05 eq.) in MeCN (1 mL) was added. The mixture was stirred at r.t. for 18 hours. 1M aq. NaOH (0.50 mL) was added and the solution was stirred at r.t. for 18 hours. The solution was neutralized with formic acid (ca. 1 mL) and then purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo (Genevac) to give the desired acid.

Listed in Table 33 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding amine of Structure 2 and the corresponding isocyanate as starting materials.

TABLE 33 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 552 (±)-{4-Chloro-2-[2-(2-fluoro- C24H20 0.97 455.2 benzylcarbamoyl)-2,3-dihydro-1H- N2O4ClF LC-MS 1FA isoindol-1-yl]-phenoxy}-acetic acid 454.88 553 (±)-{4-Chloro-2-[2-(3-fluoro- C24H20 0.98 455.2 benzylcarbamoyl)-2,3-dihydro-1H- N2O4ClF LC-MS 1FA isoindol-1-yl]-phenoxy}-acetic acid 454.88 554 (±)-{4-Chloro-2-[2-(4-fluoro- C24H20 0.98 455.2 benzylcarbamoyl)-2,3-dihydro-1H- N2O4ClF LC-MS 1FA isoindol-1-yl]-phenoxy}-acetic acid 454.88 555 (±)-[2-(2-Benzylcarbamoyl-2,3- C24H21 0.97 437.2 dihydro-1H-isoindol-1-yl)-4-chloro- N2O4Cl LC-MS 1FA phenoxy]-acetic acid 436.89 556 (±)-[4-Chloro-2-(2- C25H23 1.00 451.2 phenethylcarbamoyl-2,3-dihydro- N2O4Cl LC-MS 1FA 1H-isoindol-1-yl)-phenoxy]-acetic 450.92 acid 557 (±)-{4-Chloro-2-[2-(2-chloro- C24H20 1.01 471.2 benzylcarbamoyl)-2,3-dihydro-1H- N2O4Cl2 LC-MS 1FA isoindol-1-yl]-phenoxy}-acetic acid 471.34

Phenol Alkylation and Subsequent Saponification

To a solution of (±)-4,5-dichloro-1-(5-chloro-2-hydroxy-phenyl)-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester (25 mg, 0.06 mmol, 1.0 eq.) and cesium carbonate (37 mg, 0.11 mmol, 2.0 eq.) in DMF (1.0 mL), ethyl bromoacetate (7.5 μL, 0.07 mmol, 1.2 eq.) was added. The resulting solution was stirred at r.t. for 18 hours. 1M aq. NaOH (0.50 mL) was added. The mixture was stirred at r.t. for 2 hours. The solution was neutralized with formic acid (0.50 mL) and then purified by prep. HPLC (column: Atlantis, 18×50 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid.

Listed in Table 34 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding phenols 30 as starting materials.

TABLE 34 t_(R) [min] MS-data Formula LC-MS m/z Example Compound of Formula (I) MW Method [M + H]⁺ 558 (±)-1-(2-Carboxymethoxy-5- C24H18 1.24 506.1 chloro-phenyl)-4,5-dichloro-1,3- NO5Cl3 LC-MS 1FA dihydro-isoindole-2-carboxylic acid 506.77 benzyl ester 559 (±)-1-(2-Carboxymethoxy-5- C24H18 1.14 474.1 chloro-phenyl)-4,5-difluoro-1,3- NO5ClF2 LC-MS 1FA dihydro-isoindole-2-carboxylic acid 473.86 benzyl ester

Example 560 {4-Chloro-2-[(S)-2-((1R,2R)-2-o-tolyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid (C28H26NO4C1, MW=475.97) and Example 561 {4-Chloro-2-[(S)-2-((1S,2S)-2-o-tolyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid (C28H26NO4C1, MW=475.97)

{4-Chloro-2-[(S)-2-(trans-2-o-tolyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid (mixture of 2 diastereoisomers) was separated by chiral prep. HPLC (column: (R,R)-Whelk-01, 5 um, 21.1×250 mm, Hept/EtOH+0.1% TFA 6:4, flow 16 mL/min) to give {4-chloro-2-[(S)-2-((1R,2R)-2-o-tolyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid (LC-MS 1FA: t_(R)=1.15 min; [M+H]⁺=476.3) and {4-chloro-2-[(S)-2-((1S,2S)-2-o-tolyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid (LC-MS 1FA: t_(R)=1.18 min; [M+H]⁺=476.3).

Example 562 (4-Chloro-2-{(S)-2-[(1R,2R)-2-(2-trifluoromethyl-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid (C28H23NO4ClF3, MW=529.94) and Example 563 (4-Chloro-2-{(S)-2-[(1S,2S)-2-(2-trifluoromethyl-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid (C28H23NO4ClF3, MW=529.94)

(4-Chloro-2-{(S)-2-[trans-2-(2-trifluoromethyl-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid (mixture of 2 diastereoisomers) was separated by chiral prep. HPLC (column: (R,R)-Whelk-01, 5 um, 21.1×250 mm, Hept/EtOH+0.1% TFA 7:3, flow 16 mL/min) to give (4-chloro-2-{(S)-2-[(1R,2R)-2-(2-trifluoromethyl-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid (LC-MS 1FA: t_(R)=1.17 min; [M+H]⁺=530.3) and (4-chloro-2-{(S)-2-[(1S,2S)-2-(2-trifluoromethyl-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid (LC-MS 1FA: t_(R)=1.19 min; [M+H]⁺=530.3).

Example 564 (4-Chloro-2-{(S)-2-[(1R,2R)-2-(3-chloro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid (C27H23NO4C12, MW=496.39)

(4-Chloro-2-{(S)-2-[trans-2-(3-chloro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid (mixture of 2 diastereoisomers) was separated by chiral prep. HPLC (column: Daicel, ChiralPak IA, 5 um, 20×250 mm, Hept/EtOH+0.1% TFA 85:15, flow 16 mL/min) to give (4-chloro-2-{(S)-2-[(1R,2R)-2-(3-chloro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid (LC-MS 1FA: t_(R)=1.17 min; [M+H]⁺=496.2).

Example 565 (4-Chloro-2-{(S)-2-[(1R,2R)-2-(3-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid (C27H23NO4ClF, MW=479.93)

(4-Chloro-2-{(S)-2-[trans-2-(3-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid (mixture of 2 diastereoisomers) was separated by chiral prep. HPLC (column: Daicel, ChiralPak IA, 5 um, 20×250 mm, Hept/EtOH+0.1% TFA 8:2, flow mL/min) to give (4-chloro-2-{(S)-2-[(1R,2R)-2-(3-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid (LC-MS 1FA: t_(R)=1.12 min; [M+H]⁺=480.3).

Example 566 (4-Chloro-2-{(S)-2-[(1R,2R)-2-(4-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid (C27H23NO4ClF, MW=479.93)

(4-Chloro-2-{(S)-2-[trans-2-(4-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid (mixture of 2 diastereoisomers) was separated by chiral prep. HPLC (column: Daicel, ChiralPak IA, 5 um, 20×250 mm, Hept/EtOH+0.1% TFA 75:25, flow 16 mL/min) to give (4-chloro-2-{(S)-2-[(1R,2R)-2-(4-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid (LC-MS 1FA: t_(R)=1.12 min; [M+H]⁺=480.3).

Example 567 (S)-benzyl 1-(5-chloro-2-(2-cyanamido-2-oxoethoxy)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (C26H22N3O4Cl, MW=475.93)

To a solution of (S)-1-(2-carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (138 mg, 0.30 mmol, 1.0 eq.), cyanamide (16 mg, 0.36 mmol, 1.2 eq.), and NEt₃ (84 μL, 0.60 mmol, 2 eq.) in DMF (3.3 mL), HATU (137 mg, 0.36 mmol, 1.2 eq.) was added. The reaction mixture was stirred at r.t. for 1 hour. The mixture was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, basic conditions) and evaporated to give a pale yellow oil, contaminated with NEt₃. The contaminated product was redissolved in AcOEt and washed with 1M aq. HCl soln. and sat. aq. NaCl soln. The org. phase was dried over MgSO₄, filtered and concentrated in vacuo to give the desired product as a pale yellow oil.

LC-MS 1FA: t_(R)=1.27 min; [M+H]⁺=476.1

Example 568 (S)-1-[5-Chloro-2-(2-oxo-2-trifluoromethanesulfonylamino-ethoxy)-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C26H22N2O6ClF3S, MW=582.98)

To a solution of (S)-1-(2-carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (138 mg, 0.30 mmol, 1.0 eq.) in DMF (1.2 mL), trifluoromethanesulfonamide (47 mg, 0.30 mmol, 1.0 eq.), HATU (125 mg, 0.33 mmol, 1.1 eq.), DIPEA (103 μL, 0.60 mmol, 2.0 eq.), and DMAP (spatula tip) were added. The resulting mixture was stirred at 50° C. for 18 hours. The mixture was then purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, basic conditions) and evaporated to give a white-off solid, contaminated with some DIPEA. The contaminated product was redissolved in AcOEt and washed with 1M aq. HCl soln. and sat. aq. NaCl soln. The org. phase was dried over MgSO₄, filtered, and concentrated in vacuo to give the desired product as a white-off solid.

LC-MS 1FA: t_(R)=1.19 min; [M+H]⁺=583.1

Example 569 (S)-1-(5-Chloro-2-hydroxycarbamoylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C25H23N2O5Cl, MW=466.92)

To an ice-cooled solution of (S)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (144 mg, 0.30 mmol, 1.0 eq.) in isopropanol (1.5 mL), hydroxylamine (50% w/w aqueous solution, 1.5 mL) was added. The ice bath was removed and the reaction mixture was stirred at r.t. for 18 hours. The reaction mixture was concentrated to half and water (5 mL) was added. The resulting suspension was filtered, washed with water and dried under hv to give the desired product as a white solid.

LC-MS 1FA: t_(R)=1.13 min; [M+H]⁺=467.3

Example 570 (γ)-1-[5-Chloro-2-(1H-tetrazol-5-ylmethoxy)-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C25H22N5O3Cl, MW=475.94)

Sodium azide (49 mg, 0.75 mmol, 3 eq.) was added to a solution of (±)-1-(5-chloro-2-cyanomethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (108 mg, 0.25 mmol, 1 eq.) in DMF (4.6 mL). The reaction mixture was heated up to 100° C. and stirred at that temperature for 18 hours. The mixture was allowed to cool to r.t. and purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, basic conditions) and evaporated (genevac) to give the desired product as a white solid.

LC-MS 1 FA: t_(R)=1.21 min; [M+H]⁺=476.3

Example 571 (S)-1-[5-Chloro-2-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-ylmethoxy)-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C26H22N3O5Cl, MW=491.93)

To an ice-cooled solution of (S)-1-(5-chloro-2-hydrazinocarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (137 mg, 0.29 mmol, 1.0 eq.) and NEt₃ (82 μL, 0.59 mmol, 2.0 eq.) in THF (3 mL), 1,1′-carbonyldiimidazole (72 mg, 0.44 mmol, 1.5 eq.) was added. The reaction mixture was stirred at r.t. for 1 hour. The solvent was removed in vacuo. The residue, redissolved in DMF (2.4 mL), was purified by prep. HPLC (column: Waters X-Bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the desired product as a white foam.

LC-MS 1FA: t_(R)=1.14 min; [M+H]⁺=492.3

Example 572 (±)-1-[5-Chloro-2-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-ylmethoxy)-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C26H22N3O5Cl, MW=491.93)

A solution of (±)-1-[5-chloro-2-(N-hydroxycarbamimidoylmethoxy)-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (93 mg, 0.20 mmol, 1.0 eq.), 1,1′-carbonyldiimidazole (39 mg, 0.24 mmol, 1.2 eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (33 μL, 0.22 mmol, 1.1 eq.) in THF (2.7 mL) was heated at 120° C. under microwave irradiation for 20 min. The mixture was allowed to cool to r.t. and partitioned between AcOEt and 0.5M aq. HCl soln. The org. phase was washed with 0.5M aq. HCl soln. and sat. aq. NaCl soln., dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired product as a white solid.

LC-MS 1 FA: t_(R)=1.21 min; [M+H]⁺=492.3

Example 573 (±)-1-[5-Chloro-2-(3-hydroxy-isoxazol-5-ylmethoxy)-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C27H23N2O5Cl, MW=490.94)

To an ice-cooled solution of (±)-5-[4-chloro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxymethyl]-isoxazol-3-ol (49 mg, 0.138 mmol, 1.0 eq.) and NEt₃ (58 μL, 0.414 mmol, 3.0 eq.) in DCM (3.8 mL), benzyl chloroformate (23 μL, 0.152 mmol, 1.1 eq.) was added dropwise. Upon completion of the addition, the cooling bath was removed and the suspension was stirred at r.t. for 4 hours. The reaction was quenched with 1M aq. citric acid soln. (3.8 mL). The layers were separated. The aq. phase was extracted with DCM (3×). The comb. org. phases were concentrated in vacuo. The residue, redissolved in DMF, was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated (genevac) to give the desired product as a pale yellow solid.

LC-MS 1TFA: t_(R)=1.16 min; [M+H]⁺=491.2

Synthesis of Precursors and Intermediates General Method for the Synthesis of the Nitrostyrenes 22.

A benzaldehyde 23 (40.00 mmol, 1 eq.) was dissolved in nitromethane (23.8 mL). Molecular sieves 4A (766 mg), butylamine (0.47 mL, 4.72 mmol, 0.12 eq.) and acetic acid (0.47 ml, 8.16 mmol, 0.20 eq.) were added and the mixture was heated to 95° C. for 1 hour. The mixture was transferred into a new flask to remove the molecular sieves. The solvent was removed in vacuo. The residue was purified by CC (SiO₂, eluent: Hept/AcOEt) to give the desired nitrostyrene.

Listed in Table 35 below are nitrostyrenes 22, prepared according to the above-mentioned method, with corresponding benzaldehyde 23 as starting material.

TABLE 35 t_(R) [min] MS-data Formula LC-MS m/z Nitrostyrene 22 MW Method [M + H]⁺ 1,2-Difluoro-4-((E)-2- C8H5NO2F2 0.86 no nitro-vinyl)-benzene 185.13 LC-MS 2 ionization 2-Bromo-1-fluoro-3-((E)- C8H5NO2BrF 0.78 no 2-nitro-vinyl)-benzene 246.04 LC-MS 3 ionization 1,2-Difluoro-3-((E)-2- C8H5NO2F2 0.76 no nitro-vinyl)-benzene 185.13 LC-MS 2 ionization 2,4-Difluoro-1-((E)-2- C8H5NO2F2 0.84 no nitro-vinyl)-benzene 185.13 LC-MS 3 ionization

General Method for the Preparation of the Phenethylamines (or the Corresponding Hydrochloride Salt) 21.

H₂SO₄ (2.870 mL) was added dropwise to a stirred suspension of LiAlH₄ (4.30 g, 107.6 mmol, 4.46 eq.) in THF (162 mL) under ice-cooling. After stirring for 20 min, a solution of a nitrostyrene 22 (24.1 mmol, 1.00 eq.) in THF (17 mL) was added dropwise within 20 min under ice-cooling. After 10 min the cooling bath was removed and the mixture was warmed up gently by using a heat gun until the mixture gently boiled. After 5 min the mixture was again cooled to 0° C. The reaction was carefully quenched by the dropwise addition of iPrOH (18 mL), followed by 2M aq. NaOH (13 mL). The resulting suspension was filtered off and the filter cake was rinsed with THF. The fitrate was concentrated in vacuo to give the desired phenethylamine. The free amine was dissolved in Et₂O (88 mL) containing iPrOH (3 mL) and acidified with 2M HCl in Et₂O soln. (46 mL). The resulting suspension was filtered off. The white solids were rinsed with Et₂O and dried under high vacuum. The desired phenethylamine salt was used without further purification.

Listed in Table 36 below are phenethylamines 21 and phenethylamine hydrochlorides 21, prepared according to the above-mentioned method, with corresponding nitrostyrenes 22 as starting material.

TABLE 36 t_(R) [min] MS-data Formula LC-MS m/z Intermediates 21 MW Method [M + H]⁺ 2-(3,4-Difluoro-phenyl)- C8H9NF2 0.40 no ethylamine hydrochloride 157.07 LC-MS 2 ionization 2-(2-Bromo-3-fluoro- C8H9NBrF 0.40 218.1 phenyl)-ethylamine 218.07 LC-MS 3 2-(2,3-Difluoro-phenyl)- C8H9NF2 0.37 158.2 ethylamine hydrochloride 157.07 LC-MS 2 2-(2,4-Difluoro-phenyl)- C8H9NF2 0.43 158.0 ethylamine hydrochloride 157.07 LC-MS 3

Synthesis of 2-methyl-2-phenyl-propylamine (C₁₀H₁₅N, MW=149.24)

Step 1: To a suspension of benzyl cyanide (2.34 mL, 20.0 mmol, 1.0 eq.) and NaOH (3.22 g, 80.5 mmol, 4.0 eq.) in a mixture of DMSO (19 mL) and water (3.2 mL), methyl iodide (5.0 mL, 80.0 mmol, 4.0 eq.) was added dropwise at 0° C. The resulting mixture was stirred at r.t. for 18 hours. The mixture was partitioned between Et₂O (125 mL) and water (125 mL). The layers were separated and the aq. phase was extracted with Et₂O (2×50 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×25 mL), dried over MgSO₄, and concentrated in vacuo to give 2-methyl-2-phenyl-propionitrile. The product was used without further purification.

Step 2: To an ice-cooled suspension of LAH (1.43 g, 35.7 mmol, 1.5 eq.) in dry Et₂O (70.0 mL) under N₂, a solution of 2-methyl-2-phenyl-propionitrile (3.46 g, 23.8 mmol, 1.0 eq.) in dry Et₂O (3.0 mL) was added dropwise over 30 min. After 30 min the cooling bath was removed and the mixture was stirred at r.t. for 3 hours. The mixture was again cooled to 0° C. and carefully quenched by the dropwise addition of iPrOH (35 mL) and then 2M aq. NaOH (20 mL). The resulting suspension was filtered through celite and the filter cake was rinsed with THF. The fitrate was concentrated in vacuo. The residue was partitioned between DCM (125 mL) and 1M aq. NaOH (125 mL). The layers were separated and the aq. phase was extracted with DCM (2×50 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×25 mL), dried over MgSO₄, and concentrated in vacuo. The resulting 2-methyl-2-phenyl-propylamine was used without further purification.

LC-MS 2: t_(R)=0.39 min; [M+H]⁺=150.2 (Waters X-bridge)

General Method for the Synthesis of the 3,4-dihydroisoquinolines 11

Method A: A mixture of a phenethylamine hydrochloride 21 (12.45 mmol, 1.0 eq.), triethylamine (3.47 mL, 24.89 mmol, 2.0 eq.) and ethyl formiate (1.01 g, 13.69 mmol, 1.1 eq.) was stirred at 70° C. for 4 hours. The reaction mixture was allowed to cool to r.t. and partitioned between AcOEt (65 mL) and water (65 mL). The layers were separated. The org. phase was washed with water (1×65 mL), sat. aq. NaCl soln. (1×65 mL), dried over MgSO₄, and concentrated in vacuo to give the corresponding formamide. The formamide was dissolved in DCM (125 mL). Oxalyl chloride (1.18 mL, 13.69 mmol, 1.1 eq.) was added. The mixture was stirred at r.t. for 30 min, then cooled to −10° C. Iron(III) chloride anhydrous (2.42 g, 14.94 mmol, 1.2 eq.) was added to the cold mixture. The resulting mixture was allowed to slowly warm to r.t. and stirred at r.t. for 18 hours. The reaction was quenched with 2M aq. HCl soln. (125 mL) and the biphasic system was stirred at r.t. for 1 hour. The layers were separated. The aq. phase was extracted with DCM (1×65 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×65 mL), dried over MgSO₄, and concentrated in vacuo to give the oxazolo intermediate. The oxazolo intermediate was dissolved in MeOH (142 mL) and conc. H₂SO₄ (7.5 mL). The resulting mixture was refluxed during 3 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was partitioned between water (65 mL) and AcOEt (65 mL). The layers were separated. The org. phase was extracted with 2M aq. HCl (2×30 mL). The three comb. acidic aq. phases were basified with 25% NH₃ and extracted with DCM (3×65 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×65 mL), dried over MgSO₄ and concentrated in vacuo to give the desired 3,4-dihydro-isoquinoline as a yellow solid. The residue was used without further purification.

Listed in Table 37 below are 3,4-dihydroisoquinolines 11, prepared according to the above-mentioned method, with corresponding phenethylamines (or the corresponding hydrochloride salt) 21 as starting material.

TABLE 37 t_(R) [min] MS-data Formula LC-MS m/z Intermediates 11 MW Method [M + H]⁺ 7-Bromo-3,4-dihydro- C9H8NBr 0.44 212.3 isoquinoline 210.07 LC-MS 2 5-Bromo-3,4-dihydro- C9H8NBr 0.45 212.2 isoquinoline 210.07 LC-MS 2 6,7-Difluoro-3,4- C9H7NF2 0.31 168.0 dihydro-isoquinoline 167.16 LC-MS 2 5-Methoxy-3,4-dihydro- C10H11NO 0.41 162.1 isoquinoline 161.20 LC-MS 3 5-Fluoro-3,4-dihydro- C9H8NF 0.26 150.2 isoquinoline 149.17 LC-MS 2 6,7-Dimethoxy-3,4- C11H13NO2 0.42 192.5 dihydro-isoquinoline 191.23 LC-MS 3 7-Methoxy-3,4-dihydro- C10H11NO 0.40 161.9 isoquinoline 161.20 LC-MS 3 5-Chloro-3,4-dihydro- C9H8NCl 0.37 166.0 isoquinoline 165.62 LC-MS 3 5-Methyl-3,4-dihydro- C10H11N 0.36 146.1 isoquinoline 145.20 LC-MS 3 5-Trifluoromethyl-3,4- C10H8NF3 0.40 200.3 dihydro-isoquinoline 199.18 LC-MS 2 7-Fluoro-3,4-dihydro- C9H8NF 0.24 150.1 isoquinoline 149.17 LC-MS 3 5-Bromo-6-fluoro-3,4- C9H7NBrF 0.38 228.0 dihydro-isoquinoline 228.06 LC-MS 3 5,6-Difluoro-3,4- C9H7NF2 0.32 168.0 dihydro-isoquinoline 167.16 LC-MS 2 5,7-Difluoro-3,4- C9H7NF2 0.38 168.0 dihydro-isoquinoline 167.16 LC-MS 3 4,4-Dimethyl-3,4- C11H13N 0.45 160.1 dihydro-isoquinoline 159.23 LC-MS 3 6-Fluoro-3,4-dihydro- C9H8NF 0.36 150.2 isoquinoline 149.17 LC-MS 3

Method B: Synthesis of 3,4-dihydro-isoquinoline (C₉H₉N, MW=131.18): N-Bromosuccinimide (9.89 g, 55.0 mmol, 1.1 eq.) was added cautiously and portionwise over 20 min to a solution of 1,2,3,4-tetrahydroisoquinoline (6.34 mL, 50.0 mmol, 1.0 eq.) in DCM (130 mL) at r.t. The mixture was stirred at r.t. for 1.5 hour. 30% aq. NaOH (35 mL) was added and the mixture was stirred at r.t. for 2 hours. The organic layer was separated and washed with water (1×70 mL). The product was extracted with 10% aq. HCl (2×80 mL). The combined acidic extracts were washed with DCM (1×80 mL) and basified with 25% NH₃. The resulting mixture was extracted with DCM (2×80 mL). The comb. org. extracts were dried over MgSO₄, filtered and concentrated in vacuo to yield the 3,4-dihydroisoquinoline as an orange oil. The product was used without further purification.

LC-MS 2: t_(R)=0.23 min; [M+H]⁺=132.1

General Method for the Synthesis of the Tetrahydroisoquinolines 13.

Method A: Benzyl chloroformate (0.33 mL, 2.17 mmol, 1.0 eq.) was added to a solution of a 3,4-dihydroisoquinoline 11 (2.17 mmol, 1.0 eq.) in MeCN (4 mL) at r.t. under an argon atmosphere. After 30 min of stirring, a phenol 12 (2.17 mmol, 1.0 eq.) was added and the mixture was stirred at 70° C. for 4 days. The reaction mixture was allowed to cool to r.t., diluted with AcOEt, washed with 2M aq. HCl, water, and sat. aq. NaCl soln., dried over MgSO₄, filtered and concentrated in vacuo. The product was purified by flash master (Hept/AcOEt) to yield the desired tetrahydroisoquinoline 13 as a white foam.

Listed in Table 38 below are tetrahydroisoquinolines 13, prepared according to the above-mentioned method, with corresponding 3,4-dihydroisoquinolines 11 and phenol 12 as starting materials.

TABLE 38 t_(R) [min] MS-data Formula LC-MS m/z Intermediates 13 MW Method [M + H]⁺ (±)-1-(5-Fluoro-2-hydroxy-phenyl)-3,4- C23H20NO3F 1.07 378.1 dihydro-1H-isoquinoline-2-carboxylic 377.41 LC-MS 2 acid benzyl ester (±)-1-(5-Chloro-2-hydroxy-phenyl)-3,4- C23H20NO3Cl 1.11 394.0 dihydro-1H-isoquinoline-2-carboxylic 393.87 LC-MS 2 acid benzyl ester (±)-1-(5-Bromo-2-hydroxy-phenyl)-3,4- C23H20NO3Br 1.12 439.8 dihydro-1H-isoquinoline-2-carboxylic 438.32 LC-MS 2 acid benzyl ester (±)-1-(2-Hydroxy-5-trifluoromethyl- C24H20NO3F3 1.10 428.1 phenyl)-3,4-dihydro-1H-isoquinoline-2- 427.42 LC-MS 2 carboxylic acid benzyl ester (±)-1-(2-Hydroxy-5-methoxy-phenyl)- C24H23NO4 1.04 390.1 3,4-dihydro-1H-isoquinoline-2- 389.45 LC-MS 2 carboxylic acid benzyl ester (±)-1-(2-Hydroxy-5-methyl-phenyl)-3,4- C24H23NO3 1.09 374.1 dihydro-1H-isoquinoline-2-carboxylic 373.45 LC-MS 2 acid benzyl ester (±)-1-(2-Hydroxy-5-isopropyl-phenyl)- C26H27NO3 1.16 401.7 3,4-dihydro-1H-isoquinoline-2- 401.50 LC-MS 2 carboxylic acid benzyl ester (±)-1-(6-Hydroxy-benzo[1,3]dioxol-5-yl)- C24H21NO5 1.05 404.0 3,4-dihydro-1H-isoquinoline-2- 403.43 LC-MS 2 carboxylic acid benzyl ester (±)-7-Bromo-1-(5-fluoro-2-hydroxy- C23H19NO3BrF 1.11 456.0 phenyl)-3,4-dihydro-1H-isoquinoline-2- 456.31 LC-MS 2 carboxylic acid benzyl ester (±)-1-(4,5-Difluoro-2-hydroxy-phenyl)- C23H19NO3F2 1.10 396.0 3,4-dihydro-1H-isoquinoline-2- 395.40 LC-MS 2 carboxylic acid benzyl ester (±)-5-Fluoro-1-(5-fluoro-2-hydroxy- C23H19NO3F2 0.98 396.0 phenyl)-3,4-dihydro-1H-isoquinoline-2- 395.40 LC-MS 3 carboxylic acid benzyl ester (±)-1-(5-Fluoro-2-hydroxy-phenyl)-5- C24H22NO4F 0.99 407.9 methoxy-3,4-dihydro-1H-isoquinoline-2- 407.44 LC-MS 3 carboxylic acid benzyl ester (±)-1-(5-Fluoro-2-hydroxy-phenyl)-6,7- C25H24NO5F 0.95 438.2 dimethoxy-3,4-dihydro-1H-isoquinoline- 437.47 LC-MS 3 2-carboxylic acid benzyl ester (±)-1-(5-Fluoro-2-hydroxy-phenyl)-7- C24H22NO4F 0.97 408.0 methoxy-3,4-dihydro-1H-isoquinoline-2- 407.44 LC-MS 3 carboxylic acid benzyl ester (±)-1-(5-Cyano-2-hydroxy-phenyl)-3,4- C24H20N2O3 0.90 385.3 dihydro-1H-isoquinoline-2-carboxylic 384.43 LC-MS 2 acid benzyl ester (±)-1-(5-Fluoro-2-hydroxy-phenyl)-5- C24H22NO3F 1.08 392.0 methyl-3,4-dihydro-1H-isoquinoline-2- 391.44 LC-MS 4 carboxylic acid benzyl ester (±)-5-Chloro-1-(5-fluoro-2-hydroxy- C23H19NO3ClF 1.09 412.0 phenyl)-3,4-dihydro-1H-isoquinoline-2- 411.86 LC-MS 4 carboxylic acid benzyl ester (±)-1-(5-Bromo-2-hydroxy-phenyl)-6,7- C23H18NO3BrF2 1.02 473.8 difluoro-3,4-dihydro-1H-isoquinoline-2- 474.30 LC-MS 2 carboxylic acid benzyl ester (±)-6,7-Difluoro-1-(5-fluoro-2-hydroxy- C23H18NO3F3 0.97 413.9 phenyl)-3,4-dihydro-1H-isoquinoline-2- 413.39 LC-MS 2 carboxylic acid benzyl ester (±)-5-Bromo-1-(5-fluoro-2-hydroxy- C23H19NO3BrF 1.15 455.8 phenyl)-3,4-dihydro-1H-isoquinoline-2- 456.31 LC-MS 2 carboxylic acid benzyl ester (±)-7-Fluoro-1-(5-fluoro-2-hydroxy- C23H19NO3F2 0.89 395.9 phenyl)-3,4-dihydro-1H-isoquinoline-2- 395.40 LC-MS 3 carboxylic acid benzyl ester (±)-1-(5-Cyano-2-hydroxy-phenyl)-5,6- C24H18N2O3F2 0.93 421.6 difluoro-3,4-dihydro-1H-isoquinoline-2- 420.41 LC-MS 2 carboxylic acid benzyl ester (±)-1-(5-Dimethylsulfamoyl-2-hydroxy- C25H26N2O5S 0.90 467.2 phenyl)-3,4-dihydro-1H-isoquinoline-2- 466.56 LC-MS 2 carboxylic acid benzyl ester (±)-1-(5-Fluoro-2-hydroxy-phenyl)-5- C24H19NO3F4 1.02 446.0 trifluoromethyl-3,4-dihydro-1H- 445.41 LC-MS 2 isoquinoline-2-carboxylic acid benzyl ester (±)-5-Bromo-6-fluoro-1-(5-fluoro-2- C23H18NO3BrF2 0.93 no hydroxy-phenyl)-3,4-dihydro-1H- 474.30 LC-MS 3 ionization isoquinoline-2-carboxylic acid benzyl ester (±)-1-(5-Chloro-2-hydroxy-phenyl)-5- C23H19NO3ClF 1.03 412.2 fluoro-3,4-dihydro-1H-isoquinoline-2- 411.86 LC-MS 2 carboxylic acid benzyl ester (±)-1-(5-Cyano-2-hydroxy-phenyl)-5- C24H19N2O3F 0.92 403.3 fluoro-3,4-dihydro-1H-isoquinoline-2- 402.42 LC-MS 2 carboxylic acid benzyl ester (±)-5,6-Difluoro-1-(5-fluoro-2-hydroxy- C23H18NO3F3 0.99 414.2 phenyl)-3,4-dihydro-1H-isoquinoline-2- 413.39 LC-MS 2 carboxylic acid benzyl ester (±)-1-(5-Chloro-2-hydroxy-phenyl)-5,6- C23H18NO3ClF2 1.03 430.8 difluoro-3,4-dihydro-1H-isoquinoline-2- 429.85 LC-MS 2 carboxylic acid benzyl ester (±)-1-(3,5-Difluoro-2-hydroxy-phenyl)- C23H19NO3F2 0.99 396.2 3,4-dihydro-1H-isoquinoline-2- 395.40 LC-MS 2 carboxylic acid benzyl ester (±)-5,7-Difluoro-1-(5-fluoro-2-hydroxy- C23H18NO3F3 0.99 414.1 phenyl)-3,4-dihydro-1H-isoquinoline-2- 413.39 LC-MS 3 carboxylic acid benzyl ester (±)-1-(5-Chloro-2-hydroxy-phenyl)-5,7- C23H18NO3ClF2 1.01 430.0 difluoro-3,4-dihydro-1H-isoquinoline-2- 429.85 LC-MS 3 carboxylic acid benzyl ester (±)-1-(5-Cyano-2-hydroxy-phenyl)-5,7- C24H18N2O3F2 0.99 421.2 difluoro-3,4-dihydro-1H-isoquinoline-2- 420.41 LC-MS 4 carboxylic acid benzyl ester (±)-5-Bromo-1-(5-chloro-2-hydroxy- C23H18NO3BrClF 1.04 492.0 phenyl)-6-fluoro-3,4-dihydro-1H- 490.76 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester

Method B: To a solution of a 3,4-dihydroisoquinoline 11 (5.0 mmol, 1.0 eq.) in MeCN (15 mL), di-tert-butyl dicarbonate (1.09 g, 5.0 mmol, 1.0 eq.) was added. The resulting solution was stirred at r.t. for 2 hours. A phenol 12 (5.0 mmol, 1 eq.) was added and the mixture was stirred at 60° C. for 6 days. The reaction mixture was concentrated in vacuo. The residue was diluted with AcOEt (50 mL) and washed with 10% aq. HCl (1×25 mL), sat. aq. NaHCO₃ (1×25 mL), water (2×25 mL), sat. aq. NaCl soln. (1×25 mL), dried over MgSO₄, and concentrated in vacuo. The residue was purified by flash master (column: 100 g, flow: 40 mL/min, Heptane to Heptane+AcOEt) to yield the desired tetrahydroisoquinoline 13 as a white foam.

Listed in Table 39 below are tetrahydroisoquinolines 13, prepared according to the above-mentioned method, with corresponding 3,4-dihydroisoquinolines 11 and phenol 12 as starting materials.

TABLE 39 t_(R) [min] MS-data Formula LC-MS m/z Intermediates 13 MW Method [M + H]⁺ (±)-1-(5-Chloro-2-hydroxy-phenyl)-3,4- C20H22NO3Cl 1.06 360.2 dihydro-1H-isoquinoline-2-carboxylic 359.85 LC-MS 2 acid tert-butyl ester (±)-1-(5-Chloro-2-hydroxy-phenyl)-5- C20H21NO3ClF 1.03 378.3 fluoro-3,4-dihydro-1H-isoquinoline-2- 377.84 LC-MS 3 carboxylic acid tert-butyl ester (±)-1-(5-Chloro-2-hydroxy-phenyl)-4,4- C22H26NO3Cl 1.09 388.3 dimethyl-3,4-dihydro-1H-isoquinoline-2- 387.91 LC-MS 3 carboxylic acid tert-butyl ester (±)-1-(5-Chloro-2-hydroxy-phenyl)-6- C20H21NO3ClF 1.02 378.2 fluoro-3,4-dihydro-1H-isoquinoline-2- 377.84 LC-MS 3 carboxylic acid tert-butyl ester (±)-1-(5-Chloro-2-hydroxy-phenyl)-7- C20H21NO3ClF 1.03 378.2 fluoro-3,4-dihydro-1H-isoquinoline-2- 377.84 LC-MS 2 carboxylic acid tert-butyl ester (±)-1-(5-Chloro-2-hydroxy-phenyl)-5,6- C20H20NO3ClF2 1.03 396.1 difluoro-3,4-dihydro-1H-isoquinoline-2- 395.83 LC-MS 3 carboxylic acid tert-butyl ester (±)-5-Bromo-1-(5-chloro-2-hydroxy- C20H20NO3BrClF 1.06 457.7 phenyl)-6-fluoro-3,4-dihydro-1H- 456.74 LC-MS 3 isoquinoline-2-carboxylic acid tert-butyl ester

Synthesis of 2-allyloxy-1-bromo-4-fluoro-benzene (C9H80BrF, MW=231.06) and 1-allyloxy-2-bromo-3-fluoro-benzene (C9H80BrF, MW=231.06)

To a mixture of 2-bromo-5-fluorophenol (2.01 g, 10.5 mmol, 1.00 eq.) and potassium carbonate anhydrous (1.60 g, 11.6 mmol, 1.10 eq.) in acetone (25 mL), allyl bromide (0.97 mL, 11.1 mmol, 1.05 eq.) was added. The mixture was heated to reflux for 4 hours. The reaction mixture was allowed to cool to r.t. and poured in water (150 mL). The mixture was extracted with DCM (2×200 mL). The comb. org. phases were dried over MgSO₄ and concentrated in vacuo. The residue was purified by flash master (flow: 40 mL/min, heptane to Heptane+AcOEt) to yield the protected phenol as a colorless oil.

LC-MS 3: t_(R)=0.92 min; [M+H]⁺=no ionization

Following the same procedure, but starting from 2-bromo-3-fluorophenol, 1-allyloxy-2-bromo-3-fluoro-benzene was obtained.

LC-MS 3: t_(R)=0.92 min; [M+H]⁺=no ionization

Synthesis of (±)-1-(2-Allyloxy-4-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C26H24NO3F, MW=417.48) and (±)-1-(2-Allyloxy-6-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C26H24NO3F, MW=417.48)

To a solution under N₂ of 2-allyloxy-1-bromo-4-fluoro-benzene (462 mg, 2.00 mmol, 2.0 eq.) in THF (2 mL) cooled at −20° C., Isopropylmagnesium chloride—lithium chloride complex in THF (1:1), ca.14% in THF (320 mg, 2.20 mmol, 2.2 eq.) was added dropwise. The mixture was stirred at −20° C. for 30 min and further at 0° C. for 2 h and further at r.t. for 6 h.→Grignard Solution A

To a solution of 3,4-dihydro-isoquinoline (131 mg, 1.00 mmol, 1.0 eq.) in THF (5 mL), benzyl chloroformate (0.15 mL, 1.00 mmol, 1.0 eq.) was added. The mixture was stirred at r.t. for 30 min. The reaction was cooled to 0° C. and the Grignard solution A was added dropwise. The mixture was stirred at 0° C. for 1 hour and further at r.t. for 18 hours. The reaction was carefully quenched with 1M aq. NH₄Cl (50 mL) and with AcOEt (50 mL). The resulting suspension was filtered through celite and the filter cake was rinsed with water and AcOEt. The layers were separated and the aq. phase was extracted with AcOEt (2×50 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×50 mL), dried over MgSO₄, and concentrated in vacuo.

The residue was purified by prep. HPLC (column Water X-bridge, 30×75 mm, 10 um, UV/MS, basic conditions) and concentrated in vacuo.

LC-MS 2: t_(R)=1.05 min; [M+H]⁺=417.8

Following the same procedure, but starting from 1-allyloxy-2-bromo-3-fluoro-benzene, (±)-1-(2-allyloxy-6-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester was obtained.

LC-MS 3: t_(R)=1.04 min; [M+H]⁺=417.9

Synthesis of (±)-1-(5-Cyano-2-ethoxycarbonylmethoxy-phenyl)-6,7-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C28H24N2O5F2, MW=506.50)

To a solution of (±)-1-(5-bromo-2-ethoxycarbonylmethoxy-phenyl)-6,7-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (126 mg, 0.23 mmol, 1.00 eq.) in N,N-dimethylacetamide (0.45 mL) was added poly(methylhydrosiloxane) (5 μL) at r.t. The reaction mixture was heated to 120° C. and tris(dibenzylideneacetone) dipalladium(0) (4.5 mg, 0.005 mmol, 0.002 eq) then 1,1′-bis-(diphenylphosphino)-ferrocene (3.4 mg, 0.006 mmol, 0.027 eq.) were added. Afterwards, zinc cyanide (6.6 mg, 0.056 mmol, 0.25 eq.) was added. The resulting mixture was stirred at 150° C. during 25 min in a microwave. Zinc cyanide (3.3 mg, 0.028 mmol, 0.13 eq.), tris(dibenzylideneacetone) dipalladium(0) (2.3 mg, 0.002 mmol, 0.001 eq.) and 1,1′-bis-(diphenylphosphino)-ferrocene (1.7 mg, 0.003 mmol, 0.014 eq.) were added again. The resulting mixture was stirred at 150° C. during 25 min in a microwave. The reaction mixture was diluted with AcOEt and filtered over celite. The filtrate was washed with water, dried over MgSO₄, filtered and concentrated in vacuo. The residue was purified by CC (SiO₂, eluent:Hept/AcOEt) to yield the nitrile derivative as a pale yellow oil.

LC-MS 2: t_(R)=0.97 min; [M+H]⁺=507.3

General Method for the Synthesis of Esters of Structure 10.

Ethyl bromoacetate (0.44 mL, 3.97 mmol, 1.5 eq.) was added to a solution of a phenol 13 (2.65 mmol, 1.0 eq.) and K₂CO₃ (1.10 g, 7.95 mmol, 3.0 eq.) in DMF (9 mL) at r.t. The mixture was stirred at r.t. for 2 hours. The reaction mixture was diluted with AcOEt and water. The layers were separated and the aq. phase was extracted with AcOEt (2×). The comb. org. phases were washed with water and sat. aq. NaCl, dried over MgSO₄, filtered, and concentrated in vacuo. The crude product was purified by CC (SiO₂, Hept./AcOEt) to yield the desired ethyl ester.

Listed in Table 40 below are esters of Structure 10, prepared according to the above-mentioned method, with corresponding tetrahydroisoquinolines 13 as starting material.

TABLE 40 t_(R) [min] MS-data Formula LC-MS m/z Intermediates of Structure 10 MW Method [M + H]⁺ (±)-1-(2-Ethoxycarbonylmethoxy-5-fluoro- C27H26NO5F 0.99 464.0 phenyl)-3,4-dihydro-1H-isoquinoline-2- 463.50 LC-MS 2 carboxylic acid benzyl ester (±)-1-(2-Ethoxycarbonylmethoxy-5-methyl- C28H29NO5 1.11 460.1 phenyl)-3,4-dihydro-1H-isoquinoline-2- 459.54 LC-MS 2 carboxylic acid benzyl ester (±)-1-(2-Ethoxycarbonylmethoxy-5- C28H29NO6 1.07 476.0 methoxy-phenyl)-3,4-dihydro-1H- 475.54 LC-MS 2 isoquinoline-2-carboxylic acid benzyl ester (±)-1-(2-Ethoxycarbonylmethoxy-5- C28H26NO5F3 1.12 513.5 trifluoromethyl-phenyl)-3,4-dihydro-1H- 513.51 LC-MS 2 isoquinoline-2-carboxylic acid benzyl ester (±)-1-(5-Bromo-2-ethoxycarbonylmethoxy- C27H26NO5Br 1.13 525.9 phenyl)-3,4-dihydro-1H-isoquinoline-2- 524.41 LC-MS 2 carboxylic acid benzyl ester (±)-1-(2-Ethoxycarbonylmethoxy-5- C30H33NO5 1.17 488.2 isopropyl-phenyl)-3,4-dihydro-1H- 487.59 LC-MS 2 isoquinoline-2-carboxylic acid benzyl ester (±)-1-(6-Ethoxycarbonylmethoxy- C28H27NO7 1.06 490.1 benzo[1,3]dioxol-5-yl)-3,4-dihydro-1H- 489.52 LC-MS 2 isoquinoline-2-carboxylic acid benzyl ester (±)-1-(5-Chloro-2-ethoxycarbonylmethoxy- C27H26NO5Cl 1.04 480.1 phenyl)-3,4-dihydro-1H-isoquinoline-2- 479.96 LC-MS 2 carboxylic acid benzyl ester (±)-1-(2-Ethoxycarbonylmethoxy-4,5- C27H25NO5F2 1.10 481.5 difluoro-phenyl)-3,4-dihydro-1H- 481.49 LC-MS 2 isoquinoline-2-carboxylic acid benzyl ester (±)-5-Bromo-1-(2-ethoxycarbonylmethoxy- C27H25NO5BrF 1.16 541.9 5-fluoro-phenyl)-3,4-dihydro-1H- 542.40 LC-MS 2 isoquinoline-2-carboxylic acid benzyl ester (±)-1-(2-Ethoxycarbonylmethoxy-5-fluoro- C27H24NO5F3 1.01 500.2 phenyl)-6,7-difluoro-3,4-dihydro-1H- 499.48 LC-MS 2 isoquinoline-2-carboxylic acid benzyl ester (±)-1-(5-Cyano-2-ethoxycarbonylmethoxy- C28H26N2O5 0.94 471.0 phenyl)-3,4-dihydro-1H-isoquinoline-2- 470.52 LC-MS 2 carboxylic acid benzyl ester (±)-7-Bromo-1-(2-ethoxycarbonylmethoxy- C27H25NO5BrF 1.14 541.9 5-fluoro-phenyl)-3,4-dihydro-1H- 542.39 LC-MS 2 isoquinoline-2-carboxylic acid benzyl ester (±)-1-(5-Bromo-2-ethoxycarbonylmethoxy- C27H24NO5BrF2 1.06 559.8 phenyl)-6,7-difluoro-3,4-dihydro-1H- 560.38 LC-MS 2 isoquinoline-2-carboxylic acid benzyl ester (±)-1-(2-Ethoxycarbonylmethoxy-5-fluoro- C28H25NO5F4 1.05 532.1 phenyl)-5-trifluoromethyl-3,4-dihydro-1H- 531.50 LC-MS 2 isoquinoline-2-carboxylic acid benzyl ester (±)-1-(2-Ethoxycarbonylmethoxy-5-fluoro- C27H24NO5F3 1.03 500.2 phenyl)-5,6-difluoro-3,4-dihydro-1H- 499.48 LC-MS 2 isoquinoline-2-carboxylic acid benzyl ester (±)-1-(5-Chloro-2-ethoxycarbonylmethoxy- C27H24NO5ClF2 1.06 516.2 phenyl)-5,6-difluoro-3,4-dihydro-1H- 515.94 LC-MS 2 isoquinoline-2-carboxylic acid benzyl ester (±)-1-(5-Cyano-2-ethoxycarbonylmethoxy- C28H24N2O5F2 0.98 507.5 phenyl)-5,6-difluoro-3,4-dihydro-1H- 506.50 LC-MS 2 isoquinoline-2-carboxylic acid benzyl ester (±)-1-(5-Dimethylsulfamoyl-2- C29H32N2O7S 0.94 553.5 ethoxycarbonylmethoxy-phenyl)-3,4- 552.65 LC-MS 2 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (±)-1-(5-Chloro-2-ethoxycarbonylmethoxy- C27H25NO5ClF 1.05 498.0 phenyl)-5-fluoro-3,4-dihydro-1H- 497.95 LC-MS 2 isoquinoline-2-carboxylic acid benzyl ester (±)-1-(5-Cyano-2-ethoxycarbonylmethoxy- C28H25N2O5F 0.96 489.3 phenyl)-5-fluoro-3,4-dihydro-1H- 488.51 LC-MS 2 isoquinoline-2-carboxylic acid benzyl ester (±)-1-(5-Chloro-2-ethoxycarbonylmethoxy- C24H28NO5Cl 1.05 446.2 phenyl)-3,4-dihydro-1H-isoquinoline-2- 445.94 LC-MS 2 carboxylic acid tert-butyl ester (±)-1-(5-Chloro-2-ethoxycarbonylmethoxy- C24H27NO5ClF 1.05 464.1 phenyl)-5-fluoro-3,4-dihydro-1H- 463.93 LC-MS 3 isoquinoline-2-carboxylic acid tert-butyl ester (±)-1-(5-Chloro-2-ethoxycarbonylmethoxy- C26H32NO5Cl 1.09 474.3 phenyl)-4,4-dimethyl-3,4-dihydro-1H- 474.00 LC-MS 3 isoquinoline-2-carboxylic acid tert-butyl ester (±)-1-(5-Chloro-2-ethoxycarbonylmethoxy- C24H27NO5ClF 1.04 464.3 phenyl)-6-fluoro-3,4-dihydro-1H- 463.93 LC-MS 3 isoquinoline-2-carboxylic acid tert-butyl ester (±)-1-(5-Chloro-2-ethoxycarbonylmethoxy- C24H26NO5ClF2 1.05 482.1 phenyl)-5,6-difluoro-3,4-dihydro-1H- 481.92 LC-MS 3 isoquinoline-2-carboxylic acid tert-butyl ester (±)-1-(5-Chloro-2-ethoxycarbonylmethoxy- C24H27NO5ClF 1.05 464.3 phenyl)-7-fluoro-3,4-dihydro-1H- 463.93 LC-MS 2 isoquinoline-2-carboxylic acid tert-butyl ester

(±)-1-(5-Chloro-2-ethoxycarbonylmethoxy-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C27H25NO5ClF, MW=497.95)

To an-ice cooled solution of (±)-[4-chloro-2-(6-fluoro-1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (900 mg, 2.25 mmol, 1.0 eq.) and DIPEA (1.16 mL, 6.75 mmol, 3.0 eq.) in DCM (30 mL), benzyl chloroformate (0.43 mL, 2.92 mmol, 1.3 eq.) was added dropwise. Upon completion of the addition, the cooling bath was removed and the solution was stirred at r.t. for 3 hours. The reaction was quenched with 1M aq. citric acid soln. (25 mL). The layers were separated. The aq. phase was extracted with DCM (3×50 mL). The comb. org. phases were dried over MgSO₄ and concentrated in vacuo. The residue was purified by flash master (column: 50 g, flow: 40 mL/min, Heptane+10% EtOAc to Heptane+50% EtOAc) to yield the title compound.

LC-MS 3: t_(R)=1.05 min; [M+H]⁺=498.4

General Method for the Synthesis of Esters of Structure 10.

Step 1: (S)-2-(Toluene-4-sulfonyloxy)-propionic acid methyl ester (C11H14O5S, MW=258.29)

To an ice-cooled solution of methyl (S)-(−)-lactate (4.6 mL, 47.07 mmol, 1.0 eq.) in MeCN (25 mL), trimethylamine hydrochloride (450 mg, 4.71 mmol, 0.1 eq.) and triethylamine (7.35 mL, 52.81 mmol, 1.1 eq.) were added. A solution of p-toluenesulfonyl chloride (9.06 g, 47.07 mmol, 1.0 eq.) in MeCN (25 mL) was slowly added over 40 min at 0° C. The reaction mixture was stirred under N₂ at 0° C. for 1 hour. The mixture was filtered through celite and washed with MeCN. The filtrate was concentrated in vacuo then diluted with water (30 mL) and extracted with Et₂O (3×60 mL). The comb. org. layers were dried over MgSO₄, filtered and concentrated in vacuo to give the tosylate as a yellow liquid. The product was used crude for the next step.

LC-MS 2: t_(R)=0.84 min; [M+H]⁺=259.1

Starting from methyl (R)-(+)-lactate, (R)-2-(Toluene-4-sulfonyloxy)-propionic acid methyl ester (C11H14O5S, MW=258.29) was obtained.

Step 2: To a solution of (±)-1-(5-fluoro-2-hydroxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (500 mg, 1.33 mmol, 1.0 eq.) in MeCN (5 mL), a tosylate (1.33 mmol, 1.0 eq.) and potassium carbonate anhydrous (366 mg, 2.65 mmol, 2.0 eq.) were added and the mixture was heated to 65° C. for 18 hours. The mixture was cooled to r.t. and extracted with Et₂O (2×), dried over MgSO₄, filtered, and concentrated in vacuo. The crude product was purified by FC (SiO₂, eluent: Hept/AcOEt) to yield the ester as a mixture of 2 diastereoisomers.

Listed in Table 41 below are esters of Structure 10, prepared according to the above-mentioned method, with corresponding tetrahydroisoquinolines 13 and the corresponding tosylate as starting materials.

TABLE 41 t_(R) [min] MS-data Formula LC-MS m/z Intermediates of Structure 10 MW Method [M + H]⁺ 1-[5-Fluoro-2-((R)-1-methoxycarbonyl- C27H26NO5F 0.99 464.0 ethoxy)-phenyl]-3,4-dihydro-1H- 463.50 LC-MS 2 isoquinoline-2-carboxylic acid benzyl ester 1-[5-Fluoro-2-((S)-1-methoxycarbonyl- C27H26NO5F 1.08 464.2 ethoxy)-phenyl]-3,4-dihydro-1H- 463.50 LC-MS 2 isoquinoline-2-carboxylic acid benzyl ester 1-[5-Cyano-2-((R)-1-methoxycarbonyl- C28H26N2O5 0.94 471.2 ethoxy)-phenyl]-3,4-dihydro-1H- 470.52 LC-MS 2 isoquinoline-2-carboxylic acid benzyl ester

General Method for the Synthesis of Amines of Structure 2 or of the Corresponding Hydrochloride Salt

Method A: To a solution of (±)-1-(2-ethoxycarbonylmethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (760 mg, 1.64 mmol, 1.0 eq.) in EtOH under N₂, palladium on activated carbon (10 wt. %, 76 mg) was added. The flask was carefully evacuated and refilled with H₂ (3×). The black suspension was stirred at r.t. under an H₂-atmosphere for 18 hours. The black suspension was filtered through Celite. The Celite was rinsed with EtOH. The filtrate was concentrated in vacuo. The crude mixture was dissolved in 4M HCl in dioxane (10 mL). The resulting solution was stirred at r.t. during 30 min, then concentrated in vacuo. The new crude salt was dissolved in EtOH and concentrated in vacuo (3 times) to afford the desired salt.

Listed in Table 42 below are hydrochloride salts of Structure 2, prepared according to the above-mentioned method, with corresponding Cbz-protected tetrahydroisoquinolines of Structure 10 as starting material.

TABLE 42 t_(R) [min] MS-data Formula LC-MS m/z Intermediates of Structure 2 MW Method [M + H]⁺ (±)-[4-Fluoro-2-(1,2,3,4-tetrahydro- C19H20NO3F 0.59 330.4 isoquinolin-1-yl)-phenoxy]-acetic acid ethyl 329.14 LC-MS 2 ester hydrochloride ((S)-4-Fluoro-2-1,2,3,4-tetrahydro- C19H20NO3F 0.60 330.3 isoquinolin-1-yl-phenoxy)-acetic acid ethyl 329.14 LC-MS 2 ester hydrochloride

Method B: To an ice-cooled solution of (±)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.27 g, 2.84 mmol, 1.0 eq.) in DCM (5 mL), 4M HCl in dioxane (12 mL) was added. The resulting solution was stirred at r.t. for 7 hours. The reaction mixture was concentrated in vacuo. The residue was coevaporated with EtOH (3×). The product was triturated with Et₂O/pentane to afford the title salt.

Listed in Table 43 below are hydrochloride salts of Structure 2, prepared according to the above-mentioned method, with corresponding Boc-protected tetrahydroisoquinolines of Structure 10 as starting material.

TABLE 43 t_(R) [min] MS-data Formula LC-MS m/z Intermediates of Structure 2 MW Method [M + H]⁺ (±)-[4-Chloro-2-(1,2,3,4-tetrahydro- C19H20NO3Cl 0.64 346.1 isoquinolin-1-yl)-phenoxy]-acetic acid ethyl 345.11 LC-MS 2 ester hydrochloride (±)-[4-Chloro-2-(7-fluoro-1,2,3,4-tetrahydro- C19H19NO3ClF 0.64 364.2 isoquinolin-1-yl)-phenoxy]-acetic acid ethyl 363.10 LC-MS 2 ester hydrochloride [4-Chloro-2-((S)-5-fluoro-1,2,3,4-tetrahydro- C19H19NO3ClF 0.74 364.0 isoquinolin-1-yl)-phenoxy]-acetic acid ethyl 363.10 LC-MS 3 ester hydrochloride (±)-[4-Chloro-2-(6-fluoro-1,2,3,4-tetrahydro- C19H19NO3ClF 0.74 363.8 isoquinolin-1-yl)-phenoxy]-acetic acid ethyl 363.10 LC-MS 3 ester hydrochloride [4-Chloro-2-((S)-6-fluoro-1,2,3,4-tetrahydro- C19H19NO3ClF 0.72 364.2 isoquinolin-1-yl)-phenoxy]-acetic acid ethyl 363.10 LC-MS 3 ester hydrochloride [4-Chloro-2-((S)-5,6-difluoro-1,2,3,4- C19H18NO3ClF2 0.73 382.2 tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic 381.09 LC-MS 3 acid ethyl ester hydrochloride

Method C: To a solution of Cbz-protected tetrahydroisoquinoline of Structure 10 (1.04 mmol, 1.0 eq.) in AcOH (10 mL), 33% hydrobromic acid in acetic acid (2.5 mL) was added. The mixture was stirred at r.t. for 1 hour. The reaction mixture was concentrated in vacuo. The residue was purified by flash master (column: 100 g, flow: 45 mL/min, Heptane to AcOEt with 10% of NEt₃). The resulting amine was dissolved in EtOH (20 mL) and acetyl chloride (0.11 mL, 1.48 mmol, 1.4 eq.) was added. The resulting solution was refluxed for 2 hours, then allowed to cool to r.t., and concentrated in vacuo to give the desired hydrochloride salt.

Listed in Table 44 below are hydrochloride salts of Structure 2, prepared according to the above-mentioned method, with corresponding Cbz-protected tetrahydroisoquinolines of Structure 10 as starting material.

TABLE 44 t_(R) [min] MS-data Formula LC-MS m/z Intermediates of Structure 2 MW Method [M + H]⁺ (±)-[4-Chloro-2-(5-fluoro- C19H19NO3ClF 0.71 364.1 1,2,3,4-tetrahydro- 363.10 LC-MS 3 isoquinolin-1-yl)-phenoxy]- acetic acid ethyl ester hydrochloride ((S)-4-Chloro-2-1,2,3,4- C19H20NO3Cl 0.71 346.1 tetrahydro-isoquinolin-1- 345.11 LC-MS 3 yl-phenoxy)-acetic acid ethyl ester hydrochloride (±)-[4-Chloro-2-(1,2,3,4- C19H20NO3Cl 0.64 346.1 tetrahydro-isoquinolin-1-yl)- 345.11 LC-MS 2 phenoxy]-acetic acid ethyl ester hydrochloride

Method D: (±)-[4-Chloro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester (C19H20NO3Cl, MW=345.83): To a solution of (±)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (1.03 g, 2.15 mmol, 1.0 eq.) in AcOH (30 mL), 33% hydrobromic acid in acetic acid (7.5 mL) was added. The mixture was stirred at r.t. for 1 hour. The reaction mixture was concentrated in vacuo. The residue was purified by flash master (column: 100 g, flow: 45 mL/min, Heptane to AcOEt with 10% of NEt₃) to yield the title amine.

LC-MS 3: t_(R)=0.71 min; [M+H]⁺=346.3

Method E: (±)-[4-Fluoro-2-(6-fluoro-1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester (C19H19NO3F2, MW=347.36): To a solution of (±)-5-bromo-6-fluoro-1-(5-fluoro-2-hydroxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (50 mg, 0.11 mmol, 1.0 eq.) and Cs₂CO₃ (104 mg, 0.32 mmol, 3.0 eq.) in DMF (1 mL), ethyl bromoacetate (18 μL, 0.16 mmol, 1.5 eq.) was added. The resulting solution was stirred at r.t. for 18 hours. The solvent was evaporated and the mixture was poured into water and extracted with DCM (3×). The combined extracts were washed with water and dried over MgSO₄. To a solution under N₂ of the residue in EtOH (4 mL), palladium on activated carbon (10 wt. %, 10 mg) was added. The flask was evacuated and backfilled with H₂ (3×). The black suspension was stirred at r.t. under an H₂-atmosphere for 18 hours. The suspension was filtered through Celite, the Celite rinsed with EtOH, and the filtrate was concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters X-bridge, 19×50 mm, 10 um, UV/MS, basic conditions) to give the title amine.

LC-MS 3: t_(R)=0.62 min; [M+H]⁺=348.2

Synthesis of ((S)-4-Chloro-2-1,2,3,4-tetrahydro-isoquinolin-1-yl-phenoxy)-acetic acid ethyl ester (C19H20NO3Cl, MW=345.83)

To an ice-cooled solution of (S)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (790 mg, 1.77 mmol, 1.0 eq.) in DCM (3 mL), 4M HCl in dioxane (7.4 mL) was added. The resulting solution was stirred at r.t. for 1.5 hours. The reaction mixture was concentrated in vacuo. The residue was coevaporated with EtOH (3×). To a solution of the residue in EtOH (2 mL), conc. H₂SO₄ (0.18 mL) was added. The solution was stirred at r.t. for 18 hours. Water and 5% aq. NaOH soln. were added and the mixture was extracted with Et₂O (3×10 mL). The comb. org. phases were dried over MgSO₄, filtered, and concentrated in vacuo to give the desired product.

LC-MS 3: t_(R)=0.67 min; [M+H]⁺=346.1

Synthesis of [4-Chloro-2-((S)-6-fluoro-1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester (C19H19NO3ClF, MW=363.82)

To an ice-cooled solution of (S)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (640 mg, 1.38 mmol, 1 eq.) in EtOH (2.5 mL), 4M HCl in dioxane (5.5 mL) was added. The resulting solution was stirred at r.t. for 3 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between AcOEt and a sat. aq. NaHCO₃ soln. The layers were separated and the aq. phase was extracted with AcOEt. The comb. org. phases were concentrated in vacuo to give the free amine.

LC-MS 3: t_(R)=0.73 min; [M+H]⁺=364.2

Synthesis of (±)-[2-(1,2,3,4-Tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester (C19H21NO3, MW=311.15)

To a solution of (±)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (446 mg, 1.0 mmol, 1.0 eq.) in EtOH (4.8 mL) under N₂, palladium on activated carbon (10 wt. %, 106 mg) was added. The flask was carefully evacuated and refilled with H₂ (3×). The black suspension was stirred at 50° C. under an H₂-atmosphere for 48 hours. The black suspension was filtered through Celite. The Celite was rinsed with EtOH. The filtrate was concentrated in vacuo. To an ice-cooled solution of the residue in DCM (1.8 mL), 4M HCl in dioxane (2.6 mL) was added. The resulting solution was stirred at r.t. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was coevaporated with EtOH (3×). The residue, redissolved in DMF (2 mL), was purified by prep. HPLC (column: Atlantis, 19×30 mm, 5 um, UV/MS, acidic conditions) and evaporated to give the desired amine as a yellow oil.

LC-MS 3: t_(R)=0.69 min; [M+H]⁺=312.1

Synthesis of (±)-1-(2-Allyloxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C26H23NO3ClF, MW=451.92)

Step 1: To a mixture of (±)-5-bromo-1-(5-chloro-2-hydroxy-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (150 mg, 0.28 mmol, 1.00 eq.) and K₂CO₃ (43 mg, 0.31 mmol, 1.10 eq.) in acetone (0.7 mL), allyl bromide (26 μL, 0.29 mmol, 1.05 eq.) was added. The mixture was heated to 60° C. in a sealed vial for 18 hours. The reaction mixture was allowed to cool to r.t. and poured in water (4 mL). The mixture was extracted with DCM (2×5 mL). The comb. org. phases were dried over MgSO₄, filtered, and concentrated in vacuo. The residue was partially purified by flash master (column: 10 g, flow: 15 mL/min, Heptane to Heptane+10% AcOEt) to yield (±)-1-(2-allyloxy-5-chloro-phenyl)-5-bromo-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester as a colorless oil.

Step 2: To a solution under N₂ of (±)-1-(2-allyloxy-5-chloro-phenyl)-5-bromo-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (90 mg, 0.14 mmol, 1.00 eq.) in THF (0.28 mL) cooled at −20° C., isopropylmagnesium chloride—lithium chloride complex 14% in THF (0.32 mL, 0.14 mmol, 1.00 eq.) was added dropwise. The mixture was stirred at 0° C. and slowly warmed to r.t. over 2.5 hours. The reaction was carefully quenched with 1M aq. NH₄Cl soln. (10 mL) and with AcOEt (10 mL). The resulting suspension was filtered through celite and the filter cake was rinsed with water and AcOEt. The layers were separated and the aq. phase was extracted with AcOEt (2×10 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×10 mL), dried over MgSO₄, filtered and concentrated in vacuo.

The residue was purified by flash master (column: 10 g, flow: 15 mL/min, Heptane to Heptane+10% AcOEt) to yield (±)-1-(2-allyloxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester as a colorless oil.

LC-MS 3: t_(R)=1.07 min; [M+H]⁺=452.1

Synthesis of (±)-1-(5-Chloro-2-ethoxycarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-bromo-benzyl ester (C27H25NO5BrCl, MW=558.85)

To a solution of (±)-[4-chloro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (836 mg, 2.00 mmol, 1.0 eq.) and DIPEA (0.86 mL, 5.00 mmol, 2.5 eq.) in DCM (30 mL), carbonic acid 2-bromo-benzyl ester 2,5-dioxo-pyrrolidin-1-yl ester (787 mg, 2.40 mmol, 1.2 eq.) was added. The mixture was stirred at r.t. during 2 hours. The reaction was quenched with 1M aq. citric acid soln. (30 mL). The layers were separated. The aq. phase was extracted with DCM (3×). The comb. org. phases were dried over MgSO₄, filtered, and concentrated in vacuo. To a solution of the previous mixture in EtOH (1.1 mL), conc. H₂SO₄ (0.10 mL) was added. The solution was stirred at r.t. during 3 hours. Water and 5% aq. NaOH soln. were added and the mixture was extracted with DCM (3×). The comb. org. phases were dried over MgSO₄, filtered and concentrated in vacuo to give the desired product as a pale yellow oil.

LC-MS 3: t_(R)=1.06 min; [M+H]⁺=560.0

General Synthesis of Vinyl Amide 8.

To an ice-cooled solution of (±)-[4-chloro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (4.57 g, 10.6 mmol, 1.0 eq.) in DCM (43 mL), acryloyl chloride (0.98 mL, 11.7 mmol, 1.1 eq.) and DIPEA (3.99 mL, 23.3 mmol, 2.2 eq.) were added in sequence. The mixture was stirred at 0° C. for 1 hour. The reaction was diluted with DCM (200 mL) and 1M aq. citric acid soln. (1×200 mL). The layers were separated. The aq. phase was extracted with DCM (2×200 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×200 mL), dried over MgSO₄, filtered and concentrated in vacuo. The residue was purified by flash master (column: 100 g, flow: 45 mL/min, Heptane+20% AcOEt to Heptane+52% AcOEt) to yield the desired vinyl amide derivative.

Listed in Table 45 below are vinyl amides 8, prepared according to the above-mentioned method, with corresponding amine of Structure 2 as starting materials.

TABLE 45 t_(R) [min] MS-data Formula LC-MS m/z Vinyl amides 8 MW Method [M + H]⁺ (±)-[2-(2-Acryloyl-1,2,3,4- C22H22NO4Cl 0.93 400.3 tetrahydro-isoquinolin-1-yl)- 399.87 LC-MS 3 4-chloro-phenoxy]-acetic acid ethyl ester [2-((S)-2-Acryloyl-6-fluoro- C22H21NO4ClF 0.95 417.9 1,2,3,4-tetrahydro- 417.86 LC-MS 3 isoquinolin-1-yl)-4-chloro- phenoxy]-acetic acid ethyl ester

General Method for the Synthesis of Carbonate 5.

To a solution of 2-bromobenzyl alcohol (2.83 g, 15.0 mmol, 1.0 eq.) and DMAP (916 mg, 7.5 mmol, 0.5 eq.) in MeCN/DCM 1:1 (45 mL), N,N′-disuccinimidyl carbonate (3.84 g, 15.0 mmol, 1.0 eq.) was added. The mixture was stirred at r.t. for 18 hours. The mixture was washed with H₂O (1×45 mL), sat. aq. NaCl soln. (1×45 mL), dried over MgSO₄, filtered and concentrated in vacuo. The residue was recrystallized from iPrOH.

Listed in Table 46 below are carbonates 5, prepared according to the above-mentioned method, with corresponding benzyl alcohols 6 as starting materials.

TABLE 46 t_(R) [min] MS-data Formula LC-MS m/z Carbonates 5 MW Method [M + H]⁺ Carbonic acid 2-bromo-benzyl C12H10NO5Br 0.82 No ester 2,5-dioxo-pyrrolidin-1-yl 328.12 LC-MS 3 ionization ester Carbonic acid 2,5-dioxo- C13H13NO6 0.56 No pyrrolidin-1-yl ester 4-methoxy- 279.25 LC-MS 2 ionization benzyl ester Carbonic acid 2,5-dioxo- C12H10NO5F 0.69 No pyrrolidin-1-yl ester 4-fluoro- 267.21 LC-MS 2 ionization benzyl ester Carbonic acid 2,5-dioxo- C13H10NO5F3 0.78 No pyrrolidin-1-yl ester 4- 317.22 LC-MS 2 ionization trifluoromethyl-benzyl ester Carbonic acid 3-chloro- C12H10NO5Cl 0.74 No benzyl ester 2,5-dioxo- 283.67 LC-MS 2 ionization pyrrolidin-1-yl ester Carbonic acid 2,5-dioxo- C13H13NO5 0.73 No pyrrolidin-1-yl ester 4-methyl- 263.25 LC-MS 2 ionization benzyl ester Carbonic acid 2,3-difluoro- C12H9NO5F2 0.78 No benzyl ester 2,5-dioxo- 285.20 LC-MS 3 ionization pyrrolidin-1-yl ester Carbonic acid 2,5-dioxo- C12H10NO5F 0.78 No pyrrolidin-1-yl ester 3-fluoro- 267.21 LC-MS 3 ionization benzyl ester Carbonic acid 2,5-dioxo- C12H10NO5F 0.78 No pyrrolidin-1-yl ester 2-fluoro- 267.21 LC-MS 3 ionization benzyl ester Carbonic acid 2,5-dioxo- C13H13NO6 0.80 No pyrrolidin-1-yl ester 2- 279.25 LC-MS 3 ionization methoxy-benzyl ester

General Method for the Synthesis of Isoindoline 28.

To a solution of 2-bromobenzyl chloride (424 mg, 2.0 mmol, 1.0 eq.) in THF (15 mL) cooled at −78° C., 2.5M butyllithium solution in hexanes (0.80 mL, 2.0 mmol, 1.0 eq.) was added. The resulting yellow solution was stirred at −78° C. for 20 min. A solution of (±)-2-methyl-propane-2-sulfinic acid 1-(2-allyloxy-5-chloro-phenyl)-methylideneamide (600 mg, 2.0 mmol, 1.0 eq.) in THF (5 mL) was added dropwise at −78° C. The dark yellow solution was stirred at −78° C. for 1 hour and further at r.t. for 1 hour. H₂O (20 mL) was added and the layers were separated. The aq. layer was extracted with Et₂O (3×20 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×20 mL), dried over MgSO₄ and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, heptane to heptane+30% AcOEt) to yield the desired isoindoline 28 as a beige solid.

Listed in Table 47 below are isoindolines 28, prepared according to the above-mentioned method, with corresponding 2-bromobenzyl chloride derivatives 26 as starting materials.

TABLE 47 t_(R) [min] MS-data Formula LC-MS m/z Isoindolines 28 MW Method [M + H]⁺ 1-(2-Allyloxy-5-chloro-phenyl)-2-(2- C21H24NO2ClS 0.99 390.2 methyl-propane-2-sulfinyl)-2,3-dihydro- 389.95 LC-MS 2 1H-isoindole 1-(2-Allyloxy-5-chloro-phenyl)-5-fluoro- C21H23NO2ClFS 0.99 408.3 2-(2-methyl-propane-2-sulfinyl)-2,3- 407.94 LC-MS 3 dihydro-1H-isoindole 1-(2-Allyloxy-5-chloro-phenyl)-4-fluoro- C21H23NO2ClFS 1.00 408.3 2-(2-methyl-propane-2-sulfinyl)-2,3- 407.94 LC-MS 3 dihydro-1H-isoindole 1-(2-Allyloxy-5-chloro-phenyl)-4,5- C21H22NO2ClF2S 1.02 426.1 difluoro-2-(2-methyl-propane-2- 425.93 LC-MS 3 sulfinyl)-2,3-dihydro-1H-isoindole 1-(2-Allyloxy-5-chloro-phenyl)-4,5- C21H22NO2Cl3S 1.07 458.2 dichloro-2-(2-methyl-propane-2- 458.84 LC-MS 3 sulfinyl)-2,3-dihydro-1H-isoindole

Synthesis of (±)-2-methyl-propane-2-sulfinic acid 1-(2-allyloxy-5-chloro-phenyl)-methylideneamide (C14H18NO2CIS, MW=299.82)

Step 1: To a mixture of 5-chlorosalicylaldehyde (8.20 g, 52.37 mmol, 1.00 eq.) and potassium carbonate anhydrous (8.69 g, 62.85 mmol, 1.20 eq.) in DMF (100 mL), allyl bromide (4.7 mL, 54.99 mmol, 1.05 eq.) was added. The mixture was heated at 50° C. for 18 hours. The reaction mixture was allowed to cool to r.t. and poured in water (150 mL). The mixture was extracted with DCM (2×200 mL). The comb. org. phases were dried over MgSO₄ and concentrated in vacuo to give 2-allyloxy-5-chloro-benzaldehyde. The product was used without further purification.

Step 2: To a mixture of 2-allyloxy-5-chloro-benzaldehyde (8.55 g, 43.48 mmol, 1.0 eq.) and 2-methyl-2-propanesulfinamide (6.86 g, 56.64 mmol, 1.3 eq.) in THF (200 mL), titanium (IV) ethoxide (52.3 mL, 49.84 mmol, 1.1 eq.) was added dropwise. The reaction mixture was stirred at r.t. for 18 hours. The reaction mixture was diluted with water (1000 mL) and DCM (300 mL).The reaction mixture was filtered. The layers were separated. The aq. phase was extracted with DCM (2×200 mL). The comb. org. phases were washed with water (1×250 mL), sat. aq. NaCl soln. (1×150 mL), dried over MgSO₄, and concentrated in vacuo. The residue was used without further purification.

LC-MS 3: t_(R)=0.98 min; [M+H]⁺=300.0

General Method for the Synthesis of Isoindoline 29.

To a solution of 1-(2-allyloxy-5-chloro-phenyl)-5-fluoro-2-(2-methyl-propane-2-sulfinyl)-2,3-dihydro-1H-isoindole (230 mg, 0.56 mmol, 1.0 eq.) in MeOH (10 mL), 4M HCl in dioxane (2 mL) was added. The mixture was stirred at r.t. for 2 hours. The reaction mixture was concentrated in vacuo. To a solution of the residue and DIPEA (0.30 mL, 1.69 mmol, 3.0 eq.) in DCM (10 mL), benzyl chloroformate (0.10 mL, 0.68 mmol, 1.2 eq.) was added. The mixture was stirred at r.t. for 4 hours. The reaction mixture was diluted with 1M aq. citric acid soln. (10 mL). The layers were separated. The aq. phase was extracted with DCM (2×10 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×10 mL), dried over MgSO₄, and concentrated in vacuo. The residue was purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired isoindoline.

Listed in Table 48 below are isoindolines 29, prepared according to the above-mentioned method, with corresponding isoindoline derivatives 28 as starting materials.

TABLE 48 t_(R) [min] MS-data Formula LC-MS m/z Isoindolines 29 MW Method [M + H]⁺ (±)-1-(2-Allyloxy-5-chloro- C25H21NO3ClF 1.06 438.2 phenyl)-5-fluoro-1,3-dihydro- 437.90 LC-MS 3 isoindole-2-carboxylic acid benzyl ester (±)-1-(2-Allyloxy-5-chloro- C25H21NO3ClF 1.06 438.2 phenyl)-4-fluoro-1,3-dihydro- 437.90 LC-MS 3 isoindole-2-carboxylic acid benzyl ester (±)-1-(2-Allyloxy-5-chloro- C25H20NO3Cl3 1.11 488.1 phenyl)-4,5-dichloro-1,3- 488.80 LC-MS 3 dihydro-isoindole-2- carboxylic acid benzyl ester (±)-1-(2-Allyloxy-5-chloro- C25H20NO3ClF2 1.07 456.1 phenyl)-4,5-difluoro-1,3- 455.89 LC-MS 3 dihydro-isoindole-2- carboxylic acid benzyl ester

Synthesis of (±)-1-(2-Allyloxy-5-chloro-phenyl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (C22H24NO3C1, MW=385.89)

To a solution of (±)-1-(2-allyloxy-5-chloro-phenyl)-2-(2-methyl-propane-2-sulfinyl)-2,3-dihydro-1H-isoindole (10.77 g, 27.6 mmol, 1.0 eq.) in MeOH (300 mL), 4M HCl in dioxane (40.0 mL) was added. The mixture was stirred at r.t. for 2 hours. The reaction mixture was concentrated in vacuo. To a solution of the residue and DIPEA (14.5 mL, 82.9 mmol, 3.0 eq.) in DCM (300 mL), di-tert-butyl dicarbonate (7.23 g, 33.1 mmol, 1.2 eq.) was added. The mixture was stirred at r.t. for 4 hours. The reaction mixture was diluted 1M aq. citric acid (100 mL). The layers were separated. The aq. phase was extracted with DCM (2×100 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×100 mL), dried over MgSO₄, and concentrated in vacuo. The residue was purified by flashmaster (column: 340 g, flow: 90 mL/min, Heptane to Heptane+20% AcOEt) to yield the desired product as a white foam.

LC-MS 3: t_(R)=1.04 min; [M+H]⁺=386.1

General Method for the Synthesis of Isoindoline 30.

A mixture under N₂ of (±)-1-(2-allyloxy-5-chloro-phenyl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (10.35 g, 26.8 mmol, 1.00 eq.), 1,3-dimethylbarbituric acid (8.38 g, 53.6 mmol, 2.00 eq.) and tetrakis(triphenylphosphine) palladium (0) (1.55 g, 1.34 mmol, 0.05 eq.) in MeOH (300 mL) was stirred at r.t. for 5 hours. The mixture was partitioned between AcOEt (250 mL) and water (250 mL). The layers were separated and the aq. phase was extracted with AcOEt (2×100 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×250 mL), dried over MgSO₄, and concentrated in vacuo. The residue was purified by flash master (column: 340 g, flow: 90 mL/min, Heptane to Heptane+50% AcOEt) to give the desired phenol 30.

Listed in Table 49 below are isoindolines 30, prepared according to the above-mentioned method, with corresponding isoindoline derivatives 29 as starting materials.

TABLE 49 t_(R) [min] MS-data Formula LC-MS m/z Isoindolines 30 MW Method [M + H]⁺ (±)-1-(5-Chloro-2-hydroxy- C19H20NO3Cl 0.93 346.3 phenyl)-1,3-dihydro- 345.85 LC-MS 3 isoindole-2-carboxylic acid tert-butyl ester (±)-1-(5-Chloro-2-hydroxy- C22H17NO3ClF 0.96 398.2 phenyl)-5-fluoro-1,3-dihydro- 397.83 LC-MS 3 isoindole-2-carboxylic acid benzyl ester (±)-1-(5-Chloro-2-hydroxy- C22H17NO3ClF 0.95 398.2 phenyl)-4-fluoro-1,3- 397.83 LC-MS 3 dihydro-isoindole-2- carboxylic acid benzyl ester (±)-4,5-Dichloro-1-(5-chloro- C22H16NO3Cl3 1.01 449.6 2-hydroxy-phenyl)-1,3- 448.73 LC-MS 3 dihydro-isoindole-2- carboxylic acid benzyl ester (±)-1-(5-Chloro-2-hydroxy- C22H16NO3ClF2 0.97 416.0 phenyl)-4,5-difluoro-1,3- 415.82 LC-MS 3 dihydro-isoindole-2- carboxylic acid benzyl ester

General Synthesis of Isoindoline of Structure 10

To a mixture of (±)-1-(5-chloro-2-hydroxy-phenyl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (7.47 g, 21.6 mmol, 1.0 eq.) and potassium carbonate anhydrous (4.48 g, 32.4 mmol, 1.5 eq.) in acetone (400 mL), ethyl bromoacetate (2.63 mL, 23.8 mmol, 1.1 eq.) was added. The mixture was stirred at r.t. for 18 hours. The reaction mixture was poured in water (150 mL). The mixture was extracted with AcOEt (2×200 mL). The comb. org. phases were dried over MgSO₄ and concentrated in vacuo. The residue was purified by flash master (column: 340 g, flow: 90 mL/min, Heptane to Heptane+50% EtOAc) to yield the title product as an yellow oil.

Listed in Table 50 below are isoindolines of Structure 10, prepared according to the above-mentioned method, with corresponding isoindoline derivatives 30 as starting materials.

TABLE 50 t_(R) [min] MS-data Formula LC-MS m/z Isoindolines of Structure 10 MW Method [M + H]⁺ (±)-1-(5-Chloro-2- C23H26NO5Cl 1.01 432.3 ethoxycarbonylmethoxy- 431.91 LC-MS 3 phenyl)-1,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester (±)-1-(5-Chloro-2- C26H23NO5ClF 1.02 484.3 ethoxycarbonylmethoxy- 483.92 LC-MS 3 phenyl)-5-fluoro-1,3- dihydro-isoindole-2- carboxylic acid benzyl ester

Synthesis of [2-(2-Acryloyl-2,3-dihydro-1H-isoindol-1-yl)-4-chloro-phenoxy]-acetic acid ethyl ester (enantiomer 1) (C21H20NO4Cl, MW=385.85)

To an ice-cooled solution of (S)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (2.16 g, 5.0 mmol, 1.0 eq.) in DCM (100 mL), 4M HCl in dioxane (25 mL) was added. The resulting solution was stirred at r.t. for 18 hours. The reaction mixture was concentrated in vacuo. To a solution of the residue and NEt₃ (3.48 mL, 25 mmol, 5.0 eq.) in DCM (100 mL), acryloyl chloride (0.45 mL, 5.5 mmol, 1.1 eq.) was added. The resulting solution was stirred at r.t. for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by flash master (column: 100 g, flow: 45 mL/min, Heptane+20% AcOEt to Heptane+70% AcOEt) to give the title compound.

LC-MS 3: t_(R)=0.92 min; [M+H]⁺=385.9

Following the same procedure, but starting from 1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (enantiomer 2), [2-(2-acryloyl-2,3-dihydro-1H-isoindol-1-yl)-4-chloro-phenoxy]-acetic acid ethyl ester (enantiomer 2) was prepared.

LC-MS 3: t_(R)=0.92 min; [M+H]⁺=385.9

Synthesis of (S)-1-(5-Chloro-2-ethoxycarbonylmethoxy-phenyl)-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester (C26H24NO5C1, MW=465.93)

To an ice-cooled solution of (S)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (86 mg, 0.2 mmol, 1.00 eq.) in DCM (5 mL), 4M HCl in dioxane (5 mL) was added. The resulting solution was stirred at r.t. for 18 hours. The reaction mixture was concentrated in vacuo. To a solution of the residue and NEt₃ (0.14 mL, 1.0 mmol, 5.00 eq.) in DCM (5 mL), benzyl chloroformate (30 μL, 0.21 mmol, 1.05 eq.) was added. The resulting solution was stirred at r.t. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was purified by prep. HPLC (column: Atlantis, 18×50 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo.

LC-MS 3: t_(R)=1.03 min; [M+H]⁺=465.9

Following the same procedure, but starting from (±)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester, (±)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester was prepared.

LC-MS 3: t_(R)=1.03 min; [M+H]⁺=466.9

Synthesis of (±)-[4-Chloro-2-(2,3-dihydro-1H-isoindol-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (C18H18NO3Cl, MW=331.10)

To an ice-cooled solution of (±)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (2.26 g, 5.23 mmol, 1.0 eq.) in EtOH (100 mL), 4M HCl in dioxane (25 mL) was added. The resulting solution was stirred at r.t. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was triturated with cold methyl tert-butyl ether (50 mL), filtered, and rinsed with cold methyl tert-butyl ether (20 mL) to give the desired salt as a white solid.

LC-MS 3: t_(R)=0.70 min; [M+H]⁺=332.2

Synthesis of (±)-[4-Chloro-2-(5-fluoro-2,3-dihydro-1H-isoindol-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (C18H17NO3ClF, MW=349.09)

To a solution of (±)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-5-fluoro-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester (165 mg, 0.34 mmol, 1.0 eq.) in AcOH (3.0 mL), 33% hydrobromic acid in acetic acid (3.0 mL) was added. The mixture was stirred at r.t. for 2 hours. The reaction mixture was concentrated in vacuo. The residue was stirred in 1.25M HCl in ethanol (5.0 mL) at r.t. for 18 hours. The reaction mixture was concentrated in vacuo to give the desired salt as a colorless oil.

LC-MS 3: t_(R)=0.71 min; [M+H]⁺=350.1

Synthesis of (±)-1-(5-Fluoro-2-hydroxy-phenyl)-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester (C22H18NO3F, MW 363.39)

Step 1: To a mixture of 5-fluoro-2-hydroxybenzaldehyde (5.0 g, 35.69 mmol, 1.00 eq.) and potassium carbonate (7.97 g, 57.10 mmol, 1.60 eq.) in DMF (60 mL), benzyl bromide (4.54 mL, 37.47 mmol, 1.05 eq.) was added dropwise. The reaction mixture was refluxed for 2 hours, then allowed to cool to r.t. and poured into 100 mL of cold water and extracted with AcOEt. The organic extract was washed with 10% aq. NaOH soln. and sat. aq. NaCl soln., dried over MgSO₄ and concentrated in vacuo. The residue was purified by flash master (column: 100 g, flow: 45 mL/min, Heptane to Heptane+30% AcOEt) to yield 2-benzyloxy-5-fluoro-benzaldehyde as an yellow oil.

Step 2: To a solution under N₂ of methyl 2-iodobenzoate (1.0 g, 3.82 mmol) in THF (20 mL) cooled at −78° C., isopropylmagnesium chloride—lithium chloride complex in THF (1:1), ca. 14% in THF (554 mg, 3.82 mmol, 1.0 eq.) was added dropwise. The mixture was stirred at −78° C. for 1 hour and further at r.t. for 1 hour.==>Grignard Solution A

To the Grignard Solution A cooled to −78° C., a solution of 2-benzyloxy-5-fluoro-benzaldehyde (879 mg, 3.82 mmol, 1.0 eq.) in THF (10 mL) was added dropwise. The mixture was stirred at −78° C. for 1 hour and further at r.t. for 18 hours. The reaction was carefully quenched with 1M aq. NH₄Cl soln. (50 mL) and AcOEt (100 mL) was added. The resulting suspension was filtered through celite and the filter cake was rinsed with water and AcOEt. The layers were separated and the aq. phase was extracted with AcOEt (2×150 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×100 mL), dried over MgSO₄, and concentrated in vacuo. The residue was purified by flash master (column: 100 g, flow: 45 mL/min, Heptane to Heptane+45% AcOEt) to yield (±)-3-(2-benzyloxy-5-fluoro-phenyl)-3H-isobenzofuran-1-one as a white solid.

Step 3: To an ice-cooled and stirred suspension of lithium aluminum hydride (170 mg, 4.49 mmol, 1.5 eq.) in THF (30 mL), (±)-3-(2-benzyloxy-5-fluoro-phenyl)-3H-isobenzofuran-1-one (1.0 g, 2.99 mmol, 1.0 eq.) in THF (20 mL) was added dropwise. The mixture was stirred at 0° C. for 30 min and further at r.t. for 1 hour. The mixture was again cooled to 0° C. and carefully hydrolyzed by the dropwise addition of iPrOH (15 mL) and 2M aq. NaOH (6 mL). The resulting suspension was filtered through celite and the filter cake was rinsed with THF. The fitrate was concentrated in vacuo. The residue was diluted with 2M aq. HCl soln. (150 mL) and DCM (150 mL). The layers were separated. The aq. phase was extracted with DCM (2×50 mL). The comb. org. phases were washed with water (1×150 mL), sat. aq. NaCl soln. (1×50 mL), dried over MgSO₄, and concentrated in vacuo to give (±)-(2-benzyloxy-5-fluoro-phenyl)-(2-hydroxymethyl-phenyl)-methanol as a colorless oil.

Step 4: To an ice-cooled solution of (±)-(2-benzyloxy-5-fluoro-phenyl)-(2-hydroxymethyl-phenyl)-methanol (500 mg, 1.48 mmol, 1.00 eq.) and DMAP (9 mg, 0.07 mmol, 0.05 eq.) in DCM (30 mL), NEt₃ (0.82 mL, 5.91 mmol, 4.00 eq.) and methanesulfonyl chloride (0.24 mL, 3.10 mmol, 2.10 eq.) were added dropwise. The mixture was stirred at 0° C. for 1 hour and further at r.t. for 2 hours. The reaction mixture was diluted with H₂O (50 mL) and DCM (50 mL). The layers were separated. The aq. phase was extracted with DCM (2×50 mL). The comb. org. phases were washed with water (1×150 mL), sat. aq. NaCl soln. (1×50 mL), dried over MgSO₄, and concentrated in vacuo to give (±)-methanesulfonic acid 2-[(2-benzyloxy-5-fluoro-phenyl)-methanesulfonyloxy-methyl]-benzyl ester.

Step 5: To a solution of (±)-methanesulfonic acid 2-[(2-benzyloxy-5-fluoro-phenyl)-methanesulfonyloxy-methyl]-benzyl ester (650 mg, 1.31 mmol, 1.0 eq.) in DMF (15 mL), benzylamine (0.19 mL, 1.71 mmol, 1.3 eq.) and DIPEA (0.69 mL, 3.94 mmol, 3.0 eq.) were added in sequence. The mixture was heated at 70° C. for 2 days. The reaction mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was filtered and then purified by prep. HPLC (column: Water X-Bridge, 30×75 mm, 10 um, UV/MS, basic conditions) and concentrated in vacuo to give (±)-2-benzyl-1-(2-benzyloxy-5-fluoro-phenyl)-2,3-dihydro-1H-isoindole.

Step 6: To a solution under N₂ of (±)-2-benzyl-1-(2-benzyloxy-5-fluoro-phenyl)-2,3-dihydro-1H-isoindole (181 mg, 0.44 mmol, 1.0 eq.) in EtOH (20 mL), palladium on activated carbon (10 wt. %, 60 mg) was added. The flask was evacuated and backfilled with H₂ (3×). The black suspension was stirred at r.t. under an H₂-atmosphere for 18 hours. The suspension was filtered through Celite, the Celite rinsed with EtOH. The filtrate was concentrated in vacuo. The residue was filtered and then purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give (±)-2-(2,3-dihydro-1H-isoindol-1-yl)-4-fluoro-phenol.

Step 7: To an-ice cooled solution of (±)-2-(2,3-dihydro-1H-isoindol-1-yl)-4-fluoro-phenol (13 mg, 0.055 mmol, 1.00 eq.) and DIPEA (37 μL, 0.218 mmol, 4.00 eq.) in DCM (2 mL), benzyl chloroformate (8 μL, 0.057 mmol, 1.05 eq.) was added dropwise. Upon completion of the addition, the cooling bath was removed and the solution was stirred at r.t. for 3 hours. The reaction was quenched with 1M aq. citric acid soln. (5 mL). The layers were separated. The aq. phase was extracted with DCM (3×2 mL). The comb. org. phases were dried over MgSO₄ and concentrated in vacuo. The residue was purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give (±)-1-(5-fluoro-2-hydroxy-phenyl)-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester.

LC-MS 3: t_(R)=0.92 min; [M+H]⁺=364.1

Synthesis of (±)-1-(5-Chloro-2-cyanomethoxy-Phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C25H21N2O3 Cl, MW=432.91)

A mixture of (±)-1-(5-chloro-2-hydroxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (1.9 g, 5.00 mmol, 1.00 eq.) and chloroacetonitrile (0.34 mL, 5.19 mmol, 1.04 eq.) in DMSO (1.5 mL) was added to a suspension of potassium carbonate (980 mg, 7.09 mmol, 1.42 eq.) in DMSO (1.5 mL) (exothermic). The mixture was heated up to 80° C. and stirred at that temperature for 1 hour. The reaction mixture was poured onto ice. After the ice melted, the mixture was filtered and the filter cake was rinsed with water. The resulting yellow gum was dried under hv The product was used without further purification.

LC-MS 3: t_(R)=1.00 min; [M+H]⁺=433.1

Synthesis of (S)-1-(5-Chloro-2-hydrazinocarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C25H24N3O4Cl, MW=465.94)

To a solution of (S)-1-(2-carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (165 mg, 0.36 mmol, 1.0 eq.) in DMF (0.9 mL), TBTU (138 mg, 0.43 mmol, 1.2 eq.) and DIPEA (0.19 mL, 1.08 mmol, 3.0 eq.) were added in sequence. The resulting reaction mixture was stirred at r.t. for 15 min. Then 1M hydrazine in anhydrous THF (1.99 mL, 1.99 mmol, 5.6 eq.) was added at 0° C. (exothermic). The resulting mixture was stirred at r.t. for 18 hours. The reaction mixture was diluted with DCM and then washed with sat. aq. NaHCO₃ soln. The aq. phase was extracted once with DCM. The comb. org. phases were dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, basic conditions) and evaporated to give the desired product as a brown foam.

LC-MS 3: t_(R)=0.92 min; [M+H]⁺=466.3

Synthesis of (±)-1-[5-Chloro-2-(N-hydroxycarbamimidoylmethoxy)-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (C25H24N3O4Cl, MW=465.94)

To a solution of (±)-1-(5-chloro-2-cyanomethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (866 mg, 2.0 mmol, 1.0 eq.) in EtOH (25 mL), water (6 mL), hydroxylamine hydrochloride (542 mg, 7.6 mmol, 3.8 eq.) and potassium carbonate (485 mg, 3.5 mmol, 1.8 eq.) were added in sequence. The mixture was heated to reflux for 1 hour. The mixture was allowed to cool to r.t. and the solvent was removed in vacuo. The residue was partitioned between water and DCM. The layers were separated and the aq. layer was extracted with DCM (3×). The comb. org. layers were dried over MgSO₄, filtered, and concentrated in vacuo. The residue, redissolved in DMF (5 mL), was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, basic conditions) and evaporated to give the title product as a white foam.

LC-MS 3: t_(R)=0.84 min; [M+H]⁺=466.2

Synthesis of (±)-5-[4-Chloro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxymethyl]-isoxazol-3-ol (C19H17N2O3Cl, MW=356.81)

Step 1: To an ice-cooled solution of (3-benzyloxy-isoxazol-5-yl)-methanol (500 mg, 2.44 mmol, 1.00 eq., prepared as described by R. Riess et al. Eur. J. Org. Chem. 1998, 473-479) in DCM (5.1 mL), NEt₃ (0.39 mL, 2.8 mmol, 1.15 eq.), DMAP (3 mg, 0.02 mmol, 0.01 eq.), and methasulfonyl chloride (0.22 mL, 2.8 mmol, 1.15 eq.) were added in sequence. The reaction mixture was stirred at 0° C. for 2.5 hours, then was concentrated in vacuo to afford methanesulfonic acid 3-benzyloxy-isoxazol-5-ylmethyl ester. The product was used for the next step without further purification.

Step 2: To a solution of (±)-1-(5-chloro-2-hydroxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (159 mg, 0.4 mmol, 1 eq.) in MeCN (0.8 mL), potassium carbonate (166 mg, 1.2 mmol, 3 eq.) and methanesulfonic acid 3-benzyloxy-isoxazol-5-ylmethyl ester (113 mg, 0.4 mmol, 1 eq.) were added. The reaction mixture was stirred at 80° C. for 18 hours. The mixture was diluted with MeCN/H₂O 1:1 (1 mL) and purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give (±)-1-[2-(3-benzyloxy-isoxazol-5-ylmethoxy)-5-chloro-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester.

Step 3: A solution of (±)-1-[2-(3-benzyloxy-isoxazol-5-ylmethoxy)-5-chloro-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (70 mg, 0.12 mmol, 1 eq.) in 33% hydrobromic acid in acetic acid (0.64 mL) was stirred at r.t. for 1.5 hours. The solvent was removed in vacuo. The residue, redissolved in MeCN/MeOH, was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated (genevac) to give (±)-5-[4-chloro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxymethyl]-isoxazol-3-ol.

LC-MS 3: t_(R)=0.66 min; [M+H]⁺=357.2

General Method for the Synthesis of Phenyl Butyric Acid 45.

To a solution under N₂ of a bromobenzene 43 (5.00 mmol, 1.00 eq.) and tetrakis(triphenylphosphine) palladium (0) (289 mg, 0.25 mmol, 0.05 eq.) in THF (10 mL), 4-ethoxy-4-oxobutylzinc bromide 0.5N in THF (20 mL, 10.00 mmol, 2.00 eq.) was added. The mixture was stirred at 50° C. for 18 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, Heptane to Heptane+AcOEt) to yield the desired phenyl propionic ester. To a solution of the ester in THF (8 mL) and MeOH (2 mL), 1M aq. NaOH (4 mL) was added. The pale yellow solution was stirred at 50° C. for 18 hours, then the org. solvents were removed in vacuo. The resulting aq. layer was carefully acidified with 2N aq. HCl. The mixture was extracted with DCM (3×20 mL). The comb. org. phases were dried over MgSO₄ and concentrated in vacuo to give the desired acid. The product was used without further purification.

Listed in Table 51 below are phenyl butyric acids 45, prepared according to the above-mentioned method, with the corresponding bromobenzene 43 as starting material.

TABLE 51 t_(R) [min] MS-data Formula LC-MS m/z Intermediates 45 MW Method [M + H]⁺ 4-(2-Fluoro-phenyl)-butyric acid C10H11O2F 0.71 No 182.19 LC-MS 4 ionization 4-(3-Methoxy-phenyl)-butyric C11H14O3 0.73 No acid 194.23 LC-MS 3 ionization 4-(2-Chloro-phenyl)-butyric acid C10H11O2Cl 0.78 No 198.65 LC-MS 3 ionization 4-(3-Chloro-phenyl)-butyric acid C10H11O2Cl 0.77 No 198.65 LC-MS 3 ionization 4-o-Tolyl-butyric acid C11H14O2 0.75 No 178.23 LC-MS 3 ionization 4-m-Tolyl-butyric acid C11H14O2 0.76 No 178.23 LC-MS 3 ionization 4-(2,3-Dichloro-phenyl)-butyric C10H10O2Cl2 0.81 No acid 233.09 LC-MS 3 ionization 4-(3-Fluoro-phenyl)-butyric acid C10H11O2F 0.73 No 182.19 LC-MS 3 ionization

General Method for the Synthesis of Cyclopropanecarboxylic Acid Derivatives 49.

Step 1: A solution of 2-chlorocinnamic acid (1.84 g, 10.0 mmol, 1.0 eq.) and N,O-dimethylhydroxylamine hydrochloride (995 mg, 10.0 mmol, 1.0 eq.) in DMF (60 mL) was treated with 4-(dimethylamino)pyridine (4.89 g, 40.0 mmol, 4.0 eq.) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.88 g, 15.0 mmol, 1.5 eq.) and the resulting solution was stirred at r.t. for 62 hours. The reaction mixture was diluted with AcOEt (1 L). The diluted solution was washed with 1N aq. HCl soln. (3×400 mL), sat. aq. NaHCO₃ soln. (3×400 mL), sat. aq. NaCl soln. (1×400 mL), dried over MgSO₄, and concentrated in vacuo to give the desired amide as a pale yellow oil. The product was used without further purification.

LC-MS 3: t_(R)=0.80 min; [M+H]⁺=226.2

Step 2: To a solution under N₂ of trimethylsulfoxonium (2.20 g,10.0 mmol, 2.0 eq.) in DMSO (10 mL) maintained at r.t. with a water bath, sodium hydride (60% dispersion in mineral oil, 400 mg, 10.0 mmol, 2.0 eq.) was added portionwise over 10 min. The resulting mixture was stirred at r.t. for 1 hour. A solution of (E)-3-(2-chloro-phenyl)-N-methoxy-N-methyl-acrylamide (1.14 g g, 5.0 mmol, 1.0 eq.) in DMSO (5 mL) was added and the reaction mixture was stirred at r.t. for 19 hours. The reaction mixture was poured in sat. aq. NH₄Cl soln. (50 mL) and extracted with DCM (3×50 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×50 mL), dried over MgSO₄, and concentrated in vacuo. The residue was purified by CC (SiO₂, Hept/AcOEt) to give the desired cyclopropyl as a colorless oil.

LC-MS 2: t_(R)=0.75 min; [M+H]⁺=240.2

Step 3: To a solution of (±)-(trans)-2-(2-chloro-phenyl)-cyclopropanecarboxylic acid methoxy-methyl-amide (1.00 g, 4.20 mmol, 1.0 eq.) in Et₂O (30 mL), tert-butoxide (2.54 g, 22.66 mmol, 5.4 eq.) and H₂O (0.15 mL) were added. The mixture was stirred at r.t. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in H₂O and the solution was carefully acidified with conc. HCl. The mixture was extracted with DCM (3×20 mL). The comb. org. phases were dried over MgSO₄, filtered and concentrated in vacuo to give the desired acid as a colorless oil that solidifies upon standing. The residue was used without further purification.

Listed in Tables 52a and 52b below are cyclopropyl acids 49, prepared according to the above-mentioned method, with the corresponding α,β-unsaturated acid 46 as starting material.

TABLE 52a t_(R) [min] MS-data Formula LC-MS m/z Intermediates 49 MW Method [M + H]⁺ (±)-(trans)-2-(2-Chloro-phenyl)- C10H9O2Cl 0.67 No cyclopropanecarboxylic acid 196.63 LC-MS 2 ionization (±)-(trans)-2-(2-Fluoro-phenyl)- C10H9O2F 0.71 No cyclopropanecarboxylic acid 180.18 LC-MS 3 ionization (±)-(trans)-2-(2-Trifluoromethyl-phenyl)- C11H9O2F3 0.78 No cyclopropanecarboxylic acid 230.18 LC-MS 3 ionization (±)-(trans)-2-o-Tolyl-cyclopropanecarboxylic acid C11H12O2 0.73 No 176.21 LC-MS 3 ionization (±)-(trans)-2-(2-Methoxy-phenyl)- C11H12O3 0.71 No cyclopropanecarboxylic acid 192.21 LC-MS 3 ionization (±)-(trans)-2-(2,4-Dichloro-phenyl)- C10H8O2Cl2 0.80 No cyclopropanecarboxylic acid 231.08 LC-MS 3 ionization (±)-(trans)-2-(4-Chloro-phenyl)- C10H9O2Cl 0.76 No cyclopropanecarboxylic acid 196.63 LC-MS 3 ionization (±)-(trans)-2-(3-Chloro-phenyl)- C10H9O2Cl 0.76 No cyclopropanecarboxylic acid 196.63 LC-MS 3 ionization (±)-(trans)-2-(3-Fluoro-phenyl)- C10H9O2F 0.71 No cyclopropanecarboxylic acid 180.18 LC-MS 3 ionization (±)-(trans)-2-(3-Methoxy-phenyl)- C11H12O3 0.70 No cyclopropanecarboxylic acid 192.21 LC-MS 3 ionization (±)-(trans)-2-(3-Trifluoromethyl-phenyl)- C11H9O2F3 0.80 No cyclopropanecarboxylic acid 230.18 LC-MS 3 ionization (±)-(trans)-2-(4-Methoxy-phenyl)- C11H12O3 0.61 No cyclopropanecarboxylic acid 192.21 LC-MS 2 ionization (±)-(trans)-2-(4-Fluoro-phenyl)- C10H9O2F 0.63 No cyclopropanecarboxylic acid 180.18 LC-MS 2 ionization (±)-(trans)-2-(4-Trifluoromethyl-phenyl)- C11H9O2F3 0.74 No cyclopropanecarboxylic acid 230.18 LC-MS 2 ionization (±)-(trans)-2-p-Tolyl-cyclopropanecarboxylic acid C11H12O2 0.69 No 176.21 LC-MS 2 ionization (±)-(trans)-2-m-Tolyl- C11H12O2 0.74 No cyclopropanecarboxylic acid 176.21 LC-MS 3 ionization (±)-2,2-Dimethyl-cyclopropanecarboxylic acid C6H10O2 0.44 114.1 114.14 LC-MS 3 (±)-(trans)-2-(2,4-Dimethyl-thiazol-5-yl)- C9H11NO2S 0.33 198.1 cyclopropanecarboxylic acid 197.26 LC-MS 2

TABLE 52b Formula Intermediates 49 MW ¹H-NMR (300 MHz, CDCl₃) (±)-(trans)-2-Ethyl- C6H10O2 0.76 (ddd, J = 8.1, 6.0, 3.9, cyclopropanecarboxylic acid 114.14 1H); 0.97 (t, J = 7.3, 3H); 1.16-1.45 (m, 5H) (±)-(trans)-2-Ethoxy- C6H10O3 0.80-0.92 (m, 1H); 1.24-1.31 cyclopropanecarboxylic acid 130.14 (m, 5H); 1.70-1.76 (m, 1H); 3.60-3.64 (m, 2H) (±)-(trans)-2-Isopropyl- C7H12O2 0.80 (ddd, J = 8.1, 6.4, 3.2, cyclopropanecarboxylic acid 128.17 1H); 0.96-0.99 (m, 6H); 0.99- 1.09 (m, 1H); 1.15-1.21 (m, 1H); 1.23-1.32 (m, 1H); 1.35-1.41 (m, 1H) (±)-(trans)-2-Methyl- C5H8O2 0.73 (ddd, J = 8.0, 6.4, 4.0, cyclopropanecarboxylic acid 100.12 1H); 1.11 (d, J = 6.0, 3H); 1.18-1.25 (m, 1H); 1.28-1.34 (m, 1H); 1.38-1.49 (m, 1H)

Synthesis of {4-Chloro-2-[(S)-2-(trans-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid ethyl ester (C29H28NO4C1, MW=490.00)

A solution of the amine ((S)-4-chloro-2-1,2,3,4-tetrahydro-isoquinolin-1-yl-phenoxy)-acetic acid ethyl ester (456 mg, 1.31 mmol, 1.0 eq.) and (±)-(trans)-2-phenylcyclopropane-1-carboxylic acid (219 mg, 1.31 mmol, 1.0 eq.) in DMF (8 mL) was treated with DMAP (240 mg, 1.97 mmol, 1.5 eq.) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (377 mg, 1.97 mmol, 1.5 eq.) and the resulting solution was stirred at r.t. for 18 hours. The reaction mixture was diluted with AcOEt (150 mL). The diluted solution was washed with 1N aq. HCl (3×50 mL), sat. aq. NaHCO₃ soln. (3×50 mL), sat. aq. NaCl soln. (1×50 mL), dried over MgSO₄, filtered, and concentrated in vacuo to give the desired amide.

LC-MS 3: t_(R)=1.04 min; [M+H]⁺=490.0

General Method for the Amide Coupling Between a Cyclopropanecarboxylic Acid 49 and ((S)-4-Chloro-2-1,2,3,4-tetrahydro-isoquinolin-1-yl-phenoxy)-acetic acid ethyl ester hydrochloride and Subsequent Saponification

A solution of the amine ((S)-4-chloro-2-1,2,3,4-tetrahydro-isoquinolin-1-yl-phenoxy)-acetic acid ethyl ester hydrochloride (210 mg, 0.50 mmol, 1.0 eq.) and (±)-(trans)-2-(2-trifluoromethyl-phenyl)-cyclopropanecarboxylic acid (116 mg, 0.50 mmol, 1.0 eq.) in DMF (3 mL) was treated with DMAP (490 mg, 4.00 mmol, 8.0 eq.) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (288 mg, 1.50 mmol, 3.0 eq.) and the resulting solution was stirred at r.t. for 96 hours. The reaction mixture was diluted with AcOEt (50 mL). The diluted solution was washed with 1N aq. HCl (3×20 mL), sat. aq. NaHCO₃ soln. (3×20 mL), sat. aq. NaCl soln. (1×20 mL), dried over MgSO₄, filtered and concentrated in vacuo. To a solution of the residue in THF (2 mL), 1M aq. NaOH (0.64 mL) was added. The solution was stirred at r.t. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was diluted with water and washed with AcOEt. The aq. phase was acidified with 2N aq. HCl. The mixture was extracted with DCM. The comb. org. phases were dried over MgSO₄, filtered and concentrated in vacuo to give the desired acid.

Listed in Table 53 below are examples of compounds of Formula (I), prepared according to the above-mentioned method with the corresponding acid as starting material.

TABLE 53 t_(R) [min] MS-data Formula LC-MS m/z Compounds of Formula I MW Method [M + H]⁺ (4-Chloro-2-{(S)-2-[trans-2-(2- C28H23NO4ClF3 0.98 531.1 trifluoromethyl-phenyl)- 529.94 LC-MS 3 cyclopropanecarbonyl]-1,2,3,4-tetrahydro- isoquinolin-1-yl}-phenoxy)-acetic acid {4-Chloro-2-[(S)-2-(trans-2-o-tolyl- C28H26NO4Cl 0.97 476.1 cyclopropanecarbonyl)-1,2,3,4-tetrahydro- 475.97 LC-MS 3 isoquinolin-1-yl]-phenoxy}-acetic acid (4-Chloro-2-{(S)-2-[trans-2-(3-fluoro- C27H23NO4ClF 0.95 480.3 phenyl)-cyclopropanecarbonyl]-1,2,3,4- 479.93 LC-MS 3 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid (4-Chloro-2-{(S)-2-[trans-2-(3-chloro- C27H23NO4Cl2 0.97 496.3 phenyl)-cyclopropanecarbonyl]-1,2,3,4- 496.39 LC-MS 3 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid (4-Chloro-2-{(S)-2-[trans-2-(4-fluoro- C27H23NO4ClF 0.95 480.3 phenyl)-cyclopropanecarbonyl]-1,2,3,4- 479.93 LC-MS 3 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid

Synthesis of (±)-{2-[2-(2-Bromo-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxyl}-acetic acid ethyl ester (C21H21NO4BrF, MW=450.30)

To an ice-cooled solution under N₂ of (±)-[4-fluoro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (2.0 g, 5.2 mmol, 1.0 eq.) in DCM (13 mL), N-ethyldiisopropylamine (2.7 mL, 15.6 mmol, 3.0 eq.) was added. A solution of bromoacetyl bromide (0.5 mL, 5.7 mmol, 1.1 eq.) in DCM (5 mL) was added dropwise. The cooling bath was removed and the brown solution stirred at r.t. for 2 hours. The solution was diluted with AcOEt (170 mL), washed with sat. aq. NaHCO₃ soln. (1×90 mL), with sat. aq. NaCl soln. (1×90 mL), dried over MgSO₄, and concentrated in vacuo. The residue was purified by flash master (column: 100 g, flow: 35 mL/min, heptane to heptane+AcOEt) to yield the title compound as a brown oil.

LC-MS 2: t_(R)=0.86 min; [M+H]⁺=449.6

Synthesis of (±)-{2-[2-(2-Benzyloxycarbonylamino-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic acid ethyl ester (C29H29N2O6F, MW=520.56)

A solution of N-carbobenzyloxyglycine (1.07 g, 5.00 mmol, 1.0 eq.) and (±)-[4-fluoro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (1.93 g, 5.00 mmol, 1.0 eq.) in DMF (30 mL) was treated with 4-(dimethylamino)pyridine (2.44 g, 20.00 mmol, 4.0 eq.) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.44 g, 7.50 mmol, 1.5 eq.) and the resulting solution was stirred at r.t. for 18 hours. The reaction mixture was diluted with AcOEt (500 mL). The diluted solution was washed with 1N aq. HCl soln. (3×200 mL), sat. aq. NaHCO₃ soln. (3×200 mL), sat. aq. NaCl soln. (1×200 mL), dried over MgSO₄, and concentrated in vacuo. The crude product was purified by flash master (column: 100 g, flow: 35 mL/min, heptane to heptane+AcOEt) to yield the title product as a white foam.

LC-MS 2: t_(R)=0.92 min; [M+H]⁺=521.1

Synthesis of (±)-{2-[2-(2-Amino-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic acid ethyl ester hydrochloride (C21H24N2O4ClF, MW=422.88)

To a solution under N₂ of (±)-{2-[2-(2-benzyloxycarbonylamino-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic acid ethyl ester (1.81 g, 3.48 mmol, 1.0 eq.) in EtOH (17 mL), palladium on activated carbon (10% wt., 181 mg) was added. The flask was carefully evacuated and backfilled with H₂ (3×). The black suspension was stirred at r.t. under an H₂-atmosphere for 18 hours. The black suspension was filtered through Celite. The Celite was rinsed with EtOH. The filtrate was concentrated in vacuo. The residue was dissolved in 4M HCl in dioxane (20 mL). The resulting solution was stirred at r.t. during 30 min, then concentrated in vacuo. The crude salt was dissolved in EtOH and concentrated in vacuo (3 times) to afford the title salt as a pale yellow foam.

LC-MS 2: t_(R)=0.64 min; [M+H]⁺=387.2

General Method for the Synthesis of Indazoles 9.

To a solution of 4′-chloro-2′-fluoroacetophenone (0.7 mL, 5 mmol, 1 eq.) in DME (5 mL), hydrazine monohydrate (5 mL, 5 mmol, 1 eq.) was added at r.t. over 5 min. The reaction mixture was then refluxed in a sealed microwave vial for 24 hours. The mixture was cooled down to r.t. and the solvent was removed in vacuo. Water was added. The resulting suspension was filtered off and the solids were purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the desired indazole as a white solid.

Listed in Table 54 below are indazoles 9, prepared according to the above-mentioned method, with the corresponding 2′-fluoroacetophenone as starting material.

TABLE 54 t_(R) [min] MS-data Formula LC-MS m/z Intermediates 27 MW Method [M + H]⁺ 6-Chloro-3-methyl-1H-indazole C8H7N2Cl 0.74 167.1 166.61 LC-MS 3 4-Chloro-3-methyl-1H-indazole C8H7N2Cl 0.75 167.1 166.61 LC-MS 3 7-Fluoro-3-methyl-1H-indazole C8H7N2F 0.68 151.2 150.16 LC-MS 3 4-Fluoro-3-methyl-1H-indazole C8H7N2F 0.70 151.2 150.16 LC-MS 3 6-Fluoro-3-methyl-1H-indazole C8H7N2F 0.68 151.2 150.16 LC-MS 3

Chiral Separation

Listed in table 55 are enantiomers or diastereoisomers which were separated by prep. HPLC over a chiral stationary phase. Conditions for the separation are:

Method CS1: Column DaiCel ChiralPak IB (20×250 mm, 5 μm), eluent A 90% Heptane and eluent B 10% EtOH, flow 16 mL/min. Method CS2: Column DaiCel ChiralPak IB (20×250 mm, 5 μm), eluent A 95% Heptane and eluent B 15% EtOH, flow 16 mL/min. Method CS3: Column DaiCel ChiralPak OD (20×250 mm, 10 μm), eluent A 95% Heptane and eluent B 5% EtOH, flow 16 mL/min. Method CS4: Column DaiCel ChiralPak AD-H (20×250 mm, 5 μm), eluent A 60% Heptane and eluent B 40% EtOH, flow 16 mL/min. Method CS5: Column DaiCel ChiralPak AD-H (20×250 mm, 5 μm), eluent A 95% Heptane and eluent B 5% EtOH, flow 16 mL/min. Method CS6: Column DaiCel ChiralPak OD-H (20×250 mm, 5 μm), eluent A 85% Heptane and eluent B 15% EtOH, flow 16 mL/min. Method CS7: Column DaiCel ChiralPak AD-H (20×250 mm, 5 μm), eluent A 85% Heptane and eluent B 15% EtOH, flow 16 mL/min. Method CS8: Column DaiCel ChiralPak AD-H (20×250 mm, 5 μm), eluent A 80% Heptane and eluent B 20% EtOH, flow 16 mL/min. Method CS9: Column DaiCel ChiralPak AD-H (30×250 mm, 5 μm), eluent A 90% Heptane and eluent B 10% EtOH, flow 34 mL/min.

TABLE 55 Formula t_(R) [min] MS-data MW LC-MS m/z Optically pure intermediates HPLC Method Method [M + H]⁺ (S)-1-(5-Cyano-2-ethoxycarbonylmethoxy- C28H26N2O5 0.94 471.1 phenyl)-3,4-dihydro-1H-isoquinoline-2- 470.52 LC-MS 2 carboxylic acid benzyl ester CS1 (S)-1-(2-Ethoxycarbonylmethoxy-5-fluoro- C27H26NO5F 0.99 464.0 phenyl)-3,4-dihydro-1H-isoquinoline-2- 463.50 LC-MS 2 carboxylic acid benzyl ester CS2 (S)-1-(5-Chloro-2-ethoxycarbonylmethoxy- C27H26NO5Cl 1.04 480.1 phenyl)-3,4-dihydro-1H-isoquinoline-2- 479.96 LC-MS 2 carboxylic acid benzyl ester CS2 (S)-1-[5-Fluoro-2-((S)-1-methoxycarbonyl- C27H26NO5F 1.08 464.2 ethoxy)-phenyl]-3,4-dihydro-1H- 463.50 LC-MS 2 isoquinoline-2-carboxylic acid benzyl ester CS3 (S)-1-[5-Fluoro-2-((R)-1-methoxycarbonyl- C27H26NO5F 1.09 464.1 ethoxy)-phenyl]-3,4-dihydro-1H- 463.50 LC-MS 2 isoquinoline-2-carboxylic acid benzyl ester CS3 (S)-1-(5-Chloro-2-ethoxycarbonylmethoxy- C27H25NO5ClF 1.06 498.1 phenyl)-5-fluoro-3,4-dihydro-1H- 497.95 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester CS4 {4-Fluoro-2-[(S)-2-((trans)-2-phenyl- C29H28NO4F 0.97 474.1 cyclopropanecarbonyl)-1,2,3,4-tetrahydro- 473.54 LC-MS 2 isoquinolin-1-yl]-phenoxy}-acetic acid ethyl CS1 ester (diastereoisomer 1) {4-Fluoro-2-[(S)-2-((trans)-2-phenyl- C29H28NO4F 0.97 474.1 cyclopropanecarbonyl)-1,2,3,4-tetrahydro- 473.54 LC-MS 2 isoquinolin-1-yl]-phenoxy}-acetic acid ethyl CS1 ester (diastereoisomer 2) (S)-1-(2-Carboxymethoxy-5-cyano-phenyl)- C26H21N2O5F 0.90 461.1 5-fluoro-3,4-dihydro-1H-isoquinoline-2- 460.46 LC-MS 3 carboxylic acid benzyl ester CS5 (S)-1-(5-Chloro-2-ethoxycarbonylmethoxy- C24H27NO5ClF 1.04 464.1 phenyl)-5-fluoro-3,4-dihydro-1H- 463.93 LC-MS 3 isoquinoline-2-carboxylic acid tert-butyl CS5 ester (S)-1-(5-Chloro-2-ethoxycarbonylmethoxy- C24H28NO5Cl 1.04 446.0 phenyl)-3,4-dihydro-1H-isoquinoline-2- 445.94 LC-MS 3 carboxylic acid tert-butyl ester CS6 (S)-1-(5-Chloro-2-ethoxycarbonylmethoxy- C24H26NO5ClF2 1.05 482.1 phenyl)-5,6-difluoro-3,4-dihydro-1H- 481.92 LC-MS 3 isoquinoline-2-carboxylic acid tert-butyl CS7 ester (S)-1-(5-Chloro-2-ethoxycarbonylmethoxy- C24H27NO5ClF 1.04 464.3 phenyl)-6-fluoro-3,4-dihydro-1H- 463.93 LC-MS 3 isoquinoline-2-carboxylic acid tert-butyl CS7 ester (S)-1-(5-Chloro-2-ethoxycarbonylmethoxy- C27H24NO5ClF2 1.05 516.1 phenyl)-5,6-difluoro-3,4-dihydro-1H- 515.94 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester CS8 (S)-1-(5-Chloro-2-ethoxycarbonylmethoxy- C27H25NO5ClF 1.05 497.6 phenyl)-6-fluoro-3,4-dihydro-1H- 497.95 LC-MS 3 isoquinoline-2-carboxylic acid benzyl ester CS8 1-(5-Chloro-2-ethoxycarbonylmethoxy- C23H26NO5Cl 1.01 432.3 phenyl)-1,3-dihydro-isoindole-2-carboxylic 431.91 LC-MS 3 acid tert-butyl ester (enantiomer 1) CS9 1-(5-Chloro-2-ethoxycarbonylmethoxy- C23H26NO5Cl 1.01 432.3 phenyl)-1,3-dihydro-isoindole-2-carboxylic 431.91 LC-MS 3 acid tert-butyl ester (enantiomer 2) CS9 {4-Chloro-2-[(S)-2-((1R,2R)-2-phenyl- C29H28NO4Cl 1.04 490.0 cyclopropanecarbonyl)-1,2,3,4-tetrahydro- 490.00 LC-MS 3 isoquinolin-1-yl]-phenoxy}-acetic acid ethyl CS1 ester

Determination of the Stereochemistry

The assessment of the absolute configuration on the tetrahydroisoquinoline was done by X-ray analysis of compound 50 which was obtained according to the procedure as described in Scheme 20. The racemic phenol 51 was subjected to an alkylation with the enantiopure tosylate 52 (obtained upon treatment of the corresponding commercially available alcohol with tosyl chloride in the presence of NEt₃ and triethylamine hydrochloride), with the assumption that the alkylation goes via inversion. The resulting mixture of diastereoisomers 53 was separated by chiral prep. HPLC (Conditions: Column Daicel ChiralPak OD (20×250 mm, 10 μm), eluent A 95% Heptane and eluent B 5% EtOH, flow 16 mL/min) to afford the two enantiomerically pure esters, which were saponified to the acids 50 and 54. The acid 50 was more active in the CRTH2 binding assay; it has been crystallized by slow evaporation of a solution in DCM and used for X-ray analysis.

The assessment of the absolute configuration on the phenylcyclopropyl ring was done by following the asymmetric synthesis developed by Charette et al. (JACS1998, 120, 11943-11952). The commercially available cinnamic acid 55 was esterified and reduced to give the homoallylic alcohol 56, which undergoes an asymmetric Simmons-Smith cyclopropanation in the presence of a stoichiometric amount of the ligand 57. The resulting alcohol was then oxidized to give the desired acid 58. The acid 58 was obtained with an ee of 88% and the (S,S)-assignment was confirmed by comparison with published data (S. J. Cho et al. J. Med. Chem. 2009, 52, 1885-1902). Amide coupling between acid 58 and amine 59 in the presence of EDC as activating agent and DMAP as a base, followed by saponification afforded the final compound 60. Compound 60 has been obtained with an ee of 96% and was measured to have an antagonistic activity in the radioligand displacement assay (described below) of IC₅₀=215 nM. By comparison, separation of the diasteroisomeric mixture 61 by prep. HPLC over a chiral stationary phase (Conditions: Column Daicel ChiralPak IB (20×250 mm, 5 μm), eluent A 90% Heptane and eluent B 10% EtOH, flow 16 mL/min) afforded two enantiomerically pure esters. The resulting two esters were saponified in the presence of 1M aq. NaOH to give the two optically pure acids 62 and 60; the thus obtained acid 60 has the same retention time as the acid obtained from intermediates 58 and 59 and was shown to be the less active isomer in the radioligand displacement assay (62: IC₅₀=1.39 nM; 60: IC₅₀=1000 nM). The stereochemistry of other examples containing a phenyl-cyclopropyl-carbonyl moiety, which were obtained by chiral chromatography, has been assigned in analogy, meaning that the more active isomer was assumed to have (R,R)-configuration at the two stereocenters of the cyclopropyl ring.

Biological Assays:

Preparation of hCRTH2 Receptor Membranes and Radioliqand Displacement Assay:

First, recombinant HEK293-hCRTH₂ cells were detached from culture plates into 5 ml buffer A/plate (Buffer A: 5 mM Tris, 1 mM MgCl₂-6H₂O pH=7.4) using a rubber policeman. Cells were then transferred into centrifugation tubes and centrifuged for 5 min at 400 g. The cell pellet was resuspended in the same buffer and tubes were frozen at −80° C. Cells were thawed and membrane fragments were generated by homogenization using a polytron homogenizer (30 seconds). The membrane fragments were then centrifuged at 3000 g for 20 minutes and resuspended in buffer C (Buffer C: 75 mM Tris, 25 mM MgCl₂, 250 mM Saccharose pH 7.4). Aliquots of membrane fragments were stored at −20° C.

Binding assay was performed in a final assay volume of 250 μl. First, 25 μl of test compound, previously diluted in Binding-Buffer (Binding-Buffer: 50 mM Tris-Base, 100 mM NaCl, 1 mM EDTA, 0.1% BSA (protease free), 0.01% NaN₃, 10 mM MnCl₂, pH 7.0) was placed into each well. After addition of 75 μl Binding-Buffer, 50 μl of the radioligand ³H-PGD₂ (at 2.5 nM (220.000 dpm/well) from ANAWA ART0662) was added to each well. Binding assay was started by addition of 100 μl CRTH₂ membrane fragments, reaching a final concentration of 20 μg/well. For non-specific binding, PGD₂ was added to the reaction mixture to 10 mM final concentration.

This assay mix was incubated for 90 minutes at room temperature and then filtered through a GF/C filter 96-well plate which was pre-soaked for 3 hours in 0.5% polyethyleneimine (PEI). The filter-wells were washed three times with ice cold Binding-Buffer. Then, 40 μl of Microscint-40 (Packard) was added to each well and the retained radioactivity quantified in a Topcount (Packard).

Antagonistic activities of exemplified compounds are displayed in the following Table:

IC₅₀ Example Name [nM] 1 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H- 7.6 isoquinoline-2-carboxylic acid benzyl ester 2 1-[2-((S)-1-Carboxy-ethoxy)-5-fluoro-phenyl]-3,4-dihydro-1H- 499 isoquinoline-2-carboxylic acid benzyl ester 3 (±)-1-(2-Carboxymethoxy-5-methyl-phenyl)-3,4-dihydro-1H- 62.7 isoquinoline-2-carboxylic acid benzyl ester 4 (±)-1-(5-Bromo-2-carboxymethoxy-phenyl)-3,4-dihydro-1H- 10.5 isoquinoline-2-carboxylic acid benzyl ester 5 (±)-7-Bromo-1-(2-carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro- 81.2 1H-isoquinoline-2-carboxylic acid benzyl ester 6 (±)-1-(2-Carboxymethoxy-4,5-difluoro-phenyl)-3,4-dihydro-1H- 30.1 isoquinoline-2-carboxylic acid benzyl ester 7 (±)-5-Bromo-1-(2-carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro- 7.9 1H-isoquinoline-2-carboxylic acid benzyl ester 8 1-[2-((R)-1-Carboxy-ethoxy)-5-fluoro-phenyl]-3,4-dihydro-1H- 39.5 isoquinoline-2-carboxylic acid benzyl ester 9 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-6,7-difluoro-3,4- 35.5 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 10 (±)-1-(5-Bromo-2-carboxymethoxy-phenyl)-6,7-difluoro-3,4- 74 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 11 (±)-1-(2-Carboxymethoxy-5-cyano-phenyl)-6,7-difluoro-3,4- 13.3 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 12 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-5-trifluoromethyl-3,4- 4.59 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 13 1-[2-((R)-1-Carboxy-ethoxy)-5-cyano-phenyl]-3,4-dihydro-1H- 11 isoquinoline-2-carboxylic acid benzyl ester 14 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-5,6-difluoro-3,4- 18.8 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 15 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 10.1 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 16 (±)-1-(2-Carboxymethoxy-5-cyano-phenyl)-5,6-difluoro-3,4- 4.34 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 17 (±)-1-(2-Carboxymethoxy-5-dimethylsulfamoyl-phenyl)-3,4- 889 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 18 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5-fluoro-3,4-dihydro- 5.43 1H-isoquinoline-2-carboxylic acid benzyl ester 19 (±)-1-(2-Carboxymethoxy-5-cyano-phenyl)-5-fluoro-3,4-dihydro- 9.38 1H-isoquinoline-2-carboxylic acid benzyl ester 20 (±)-1-(2-Carboxymethoxy-5-trifluoromethyl-phenyl)-3,4-dihydro- 50.7 1H-isoquinoline-2-carboxylic acid benzyl ester 21 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 6.87 isoquinoline-2-carboxylic acid benzyl ester 22 (±)-1-(2-Carboxymethoxy-5-isopropyl-phenyl)-3,4-dihydro-1H- 483 isoquinoline-2-carboxylic acid benzyl ester 23 (±)-1-(6-Carboxymethoxy-benzo[1,3]dioxol-5-yl)-3,4-dihydro-1H- 227 isoquinoline-2-carboxylic acid benzyl ester 24 (±)-1-(2-Carboxymethoxy-5-methoxy-phenyl)-3,4-dihydro-1H- 83.7 isoquinoline-2-carboxylic acid benzyl ester 25 (S)-1-(2-Carboxymethoxy-5-cyano-phenyl)-3,4-dihydro-1H- 2.52 isoquinoline-2-carboxylic acid benzyl ester 26 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 4.52 isoquinoline-2-carboxylic acid benzyl ester 27 (S)-1-[2-((R)-1-Carboxy-ethoxy)-5-fluoro-phenyl]-3,4-dihydro-1H- 12.1 isoquinoline-2-carboxylic acid benzyl ester 28 (S)-1-[2-((S)-1-Carboxy-ethoxy)-5-fluoro-phenyl]-3,4-dihydro-1H- 443 isoquinoline-2-carboxylic acid benzyl ester 29 {4-Fluoro-2-[(S)-2-((trans)-2-phenyl-cyclopropanecarbonyl)- 7.72 1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid (diastereoisomer 1) 30 {4-Fluoro-2-[(S)-2-((trans)-2-phenyl-cyclopropanecarbonyl)- 912 1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid (diastereoisomer 2) 31 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5-fluoro-3,4-dihydro- 1.41 1H-isoquinoline-2-carboxylic acid benzyl ester 32 (S)-1-(2-Carboxymethoxy-5-cyano-phenyl)-5-fluoro-3,4-dihydro- 1.99 1H-isoquinoline-2-carboxylic acid benzyl ester 33 (±)-1-(2-Carboxymethoxy-3,5-difluoro-phenyl)-3,4-dihydro-1H- 196 isoquinoline-2-carboxylic acid benzyl ester 34 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-5-fluoro-3,4-dihydro- 7.22 1H-isoquinoline-2-carboxylic acid benzyl ester 35 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-5-methoxy-3,4- 19.7 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 36 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-6,7-dimethoxy-3,4- 57.1 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 37 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-7-methoxy-3,4- 19.9 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 38 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-5-chloro-3,4-dihydro- 20.8 1H-isoquinoline-2-carboxylic acid benzyl ester 39 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-5-methyl-3,4-dihydro- 22.2 1H-isoquinoline-2-carboxylic acid benzyl ester 40 (±)-5-Bromo-1-(2-carboxymethoxy-5-fluoro-phenyl)-6-fluoro-3,4- 23 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 41 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-7-fluoro-3,4-dihydro- 24.8 1H-isoquinoline-2-carboxylic acid benzyl ester 42 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-5,7-difluoro-3,4- 6.84 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 43 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,7-difluoro-3,4- 4.94 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 44 (±)-1-(2-Carboxymethoxy-5-cyano-phenyl)-5,7-difluoro-3,4- 8.34 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 45 (±)-{2-[2-(2-Benzo[d]isoxazol-3-yl-acetyl)-1,2,3,4-tetrahydro- 369 isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic acid 46 (±)-{4-Fluoro-2-[2-(3-methyl-3-phenyl-butyryl)-1,2,3,4-tetrahydro- 916 isoquinolin-1-yl]-phenoxy}-acetic acid 47 (±)-{4-Fluoro-2-[2-(2-naphthalen-1-yl-acetyl)-1,2,3,4-tetrahydro- 198 isoquinolin-1-yl]-phenoxy}-acetic acid 48 (±)-{4-Fluoro-2-[2-(2-quinolin-7-yl-acetyl)-1,2,3,4-tetrahydro- 287 isoquinolin-1-yl]-phenoxy}-acetic acid 49 (±)-{4-Fluoro-2-[2-(2-quinolin-6-yl-acetyl)-1,2,3,4-tetrahydro- 35.7 isoquinolin-1-yl]-phenoxy}-acetic acid 50 (±)-{2-[2-(2-2,3-Dihydro-benzo[1,4]dioxin-6-yl-acetyl)-1,2,3,4- 182 tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic acid 51 (±)-{4-Fluoro-2-[2-(3-1H-indol-3-yl-propionyl)-1,2,3,4-tetrahydro- 30.1 isoquinolin-1-yl]-phenoxy}-acetic acid 52 (±)-(2-{2-[3-(1-Ethyl-2-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4- 600 tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic acid 53 (±)-(2-{2-[3-(2,6-Dichloro-phenyl)-propionyl]-1,2,3,4-tetrahydro- 877 isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic acid 54 (±)-(4-Fluoro-2-{2-[3-(2-fluoro-phenoxy)-propionyl]-1,2,3,4- 32.2 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 55 (±)-[4-Fluoro-2-(2-{2-[4-(5-methyl-tetrazol-1-yl)-phenyl]-acetyl}- 800 1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid 56 (±)-(2-{2-[3-(6-Chloro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)- 735 propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)- acetic acid 57 (±)-(4-Fluoro-2-{2-[2-(2-methyl-thiazol-4-yl)-acetyl]-1,2,3,4- 730 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 58 (±)-{2-[2-(2-Benzo[b]thiophen-3-yl-acetyl)-1,2,3,4-tetrahydro- 123 isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic acid 59 (±)-{2-[2-(3-Benzothiazol-2-yl-propionyl)-1,2,3,4-tetrahydro- 794 isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic acid 60 (±)-{2-[2-(2-Biphenyl-4-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1- 577 yl]-4-fluoro-phenoxy}-acetic acid 61 (±)-{4-Fluoro-2-[2-(2-indol-1-yl-acetyl)-1,2,3,4-tetrahydro- 846 isoquinolin-1-yl]-phenoxy}-acetic acid 62 (±)-{2-[2-(2-1H-Benzoimidazol-2-yl-acetyl)-1,2,3,4-tetrahydro- 794 isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic acid 63 (±)-{2-[2-(2-1,3-Dihydro-isoindol-2-yl-acetyl)-1,2,3,4-tetrahydro- 871 isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic acid 64 (±)-(4-Fluoro-2-{2-[3-(5-methoxy-1H-indol-3-yl)-propionyl]- 49.7 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 65 (±)-(4-Fluoro-2-{2-[3-(2-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4- 191 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 66 (±)-(4-Fluoro-2-{2-[3-(1-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4- 27.5 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 67 {4-Fluoro-2-[2-(trans-2-phenyl-cyclopropanecarbonyl)-1,2,3,4- 15.5 tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid 68 (±)-{4-Chloro-2-[2-(2-cyclopropyl-acetyl)-1,2,3,4-tetrahydro- 508 isoquinolin-1-yl]-phenoxy}-acetic acid 69 (±)-{4-Chloro-2-[2-(2H-chromene-3-carbonyl)-1,2,3,4-tetrahydro- 377 isoquinolin-1-yl]-phenoxy}-acetic acid 70 (±)-{4-Chloro-2-[2-(3-methoxy-propionyl)-1,2,3,4-tetrahydro- 139 isoquinolin-1-yl]-phenoxy}-acetic acid 71 (±)-(4-Chloro-2-{2-[2-(2-chloro-phenyl)-acetyl]-1,2,3,4-tetrahydro- 291 isoquinolin-1-yl}-phenoxy)-acetic acid 72 (±)-{4-Chloro-2-[2-(2-indol-1-yl-acetyl)-1,2,3,4-tetrahydro- 44 isoquinolin-1-yl]-phenoxy}-acetic acid 73 (±)-(4-Chloro-2-{2-[3-(2-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4- 4.13 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 74 (±)-(4-Chloro-2-{2-[3-(5-methoxy-1H-indol-3-yl)-propionyl]- 1.42 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 75 (±)-(4-Chloro-2-{2-[2-(2,6-dimethyl-pyridin-3-yloxy)-acetyl]- 3.68 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 76 (±)-(4-Chloro-2-{2-[3-(1-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4- 4.46 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 77 {4-Chloro-2-[2-(1,2,3,4-tetrahydro-naphthalene-2-carbonyl)- 134 1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid 78 (±)-{2-[2-(2-Benzoimidazol-1-yl-acetyl)-1,2,3,4-tetrahydro- 51.1 isoquinolin-1-yl]-4-chloro-phenoxy}-acetic acid 79 (±)-{4-Chloro-2-[2-(2-3,4-dihydro-2H-quinolin-1-yl-acetyl)-1,2,3,4- 62.9 tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid 80 (±)-{4-Chloro-2-[2-(2-indazol-2-yl-acetyl)-1,2,3,4-tetrahydro- 46.9 isoquinolin-1-yl]-phenoxy}-acetic acid 81 (±)-(4-Chloro-2-{2-[3-(3-trifluoromethyl-phenyl)-propionyl]-1,2,3,4- 27.5 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 82 (4-Chloro-2-{2-trans-[2-(2-chloro-phenyl)-cyclopropanecarbonyl]- 4.8 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 83 (±)-(4-Chloro-2-{2-[3-(1-phenyl-1H-imidazol-2-yl)-propionyl]- 422 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 84 (4-Chloro-2-{2-[3-(4-oxo-2-phenyl-thiazolidin-3-yl)-propionyl]- 28.4 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 85 (±)-[4-Chloro-2-(2-{3-[3-(2,3-dimethyl-phenyl)-3H-imidazol-4-yl]- 18.9 propionyl}-1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid 86 (±)-(2-{2-[2-(Biphenyl-2-yloxy)-acetyl]-1,2,3,4-tetrahydro- 422 isoquinolin-1-yl}-4-chloro-phenoxy)-acetic acid 87 (±)-(4-Chloro-2-{2-[3-(3-fluoro-phenoxy)-propionyl]-1,2,3,4- 17.8 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 88 (±)-{4-Chloro-2-[2-(3-p-tolyloxy-propionyl)-1,2,3,4-tetrahydro- 148 isoquinolin-1-yl]-phenoxy}-acetic acid 89 (±)-(4-Chloro-2-{2-[3-(4-chloro-phenoxy)-propionyl]-1,2,3,4- 37.9 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 90 (±)-(4-Chloro-2-{2-[3-(2-trifluoromethyl-phenyl)-propionyl]-1,2,3,4- 45.8 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 91 (±)-(4-Chloro-2-{2-[2-(5-fluoro-1H-indol-3-yl)-acetyl]-1,2,3,4- 113 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 92 (±)-(4-Chloro-2-{2-[2-(6-methoxy-benzofuran-3-yl)-acetyl]- 2.86 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 93 (±)-(4-Chloro-2-{2-[4-(4-chloro-phenyl)-butyryl]-1,2,3,4- 12.9 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 94 (±)-{4-Chloro-2-[2-(3-m-tolyloxy-propionyl)-1,2,3,4-tetrahydro- 16.2 isoquinolin-1-yl]-phenoxy}-acetic acid 95 (±)-(4-Chloro-2-{2-[3-(3-chloro-phenoxy)-propionyl]-1,2,3,4- 27.5 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 96 (±)-(4-Chloro-2-{2-[2-(5-chloro-1H-indol-3-yl)-acetyl]-1,2,3,4- 172 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 97 (±)-{4-Chloro-2-[2-(4-p-tolyl-butyryl)-1,2,3,4-tetrahydro- 9.7 isoquinolin-1-yl]-phenoxy}-acetic acid 98 (±)-(4-Chloro-2-{2-[2-(5-chloro-benzo[b]thiophen-3-yl)-acetyl]- 124 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 99 (±)-(4-Chloro-2-{2-[2-(5-methoxy-1H-indol-2-yl)-acetyl]-1,2,3,4- 296 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 100 (±)-(4-Chloro-2-{2-[2-(5-methyl-benzo[d]isoxazol-3-yl)-acetyl]- 205 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 101 (±)-(4-Chloro-2-{2-[2-(5-methoxy-benzo[d]isoxazol-3-yl)-acetyl]- 19.6 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 102 (±)-(4-Chloro-2-{2-[3-(4-fluoro-phenoxy)-propionyl]-1,2,3,4- 7.53 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 103 (±)-(4-Chloro-2-{2-[4-(4-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro- 11.2 isoquinolin-1-yl}-phenoxy)-acetic acid 104 (±)-{4-Chloro-2-[2-(3-o-tolyl-propionyl)-1,2,3,4-tetrahydro- 28.6 isoquinolin-1-yl]-phenoxy}-acetic acid 105 (±)-{2-[2-(2-Benzyloxy-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]- 9.95 4-chloro-phenoxy}-acetic acid 106 (±)-(4-Chloro-2-{2-[2-(2-chloro-benzyloxy)-acetyl]-1,2,3,4- 4.06 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 107 (±)-{4-Chloro-2-[2-(4-phenyl-butyryl)-1,2,3,4-tetrahydro- 20.6 isoquinolin-1-yl]-phenoxy}-acetic acid 108 (±)-(4-Chloro-2-{2-[4-(3-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro- 35.9 isoquinolin-1-yl}-phenoxy)-acetic acid 109 (±)-(4-Chloro-2-{2-[4-(2,3-dichloro-phenyl)-butyryl]-1,2,3,4- 16.9 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 110 (±)-{4-Chloro-2-[2-(4-m-tolyl-butyryl)-1,2,3,4-tetrahydro- 41.2 isoquinolin-1-yl]-phenoxy}-acetic acid 111 (±)-{4-Chloro-2-[2-(4-o-tolyl-butyryl)-1,2,3,4-tetrahydro- 45 isoquinolin-1-yl]-phenoxy}-acetic acid 112 (±)-(4-Chloro-2-{2-[4-(3-chloro-phenyl)-butyryl]-1,2,3,4- 23.4 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 113 (±)-(4-Chloro-2-{2-[4-(2-chloro-phenyl)-butyryl]-1,2,3,4- 25.5 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 114 (±)-(4-Chloro-2-{2-[4-(3-methoxy-phenyl)-butyryl]-1,2,3,4- 34.5 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 115 (±)-(4-Chloro-2-{2-[4-(2-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro- 27 isoquinolin-1-yl}-phenoxy)-acetic acid 116 {4-Chloro-2-[2-(trans-2-phenyl-cyclopropanecarbonyl)-1,2,3,4- 5.42 tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid 117 {4-Chloro-2-[5-fluoro-2-(trans-2-phenyl-cyclopropanecarbonyl)- 32.5 1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid 118 (±)-{4-Chloro-2-[5-fluoro-2-(3-o-tolyl-propionyl)-1,2,3,4- 95.4 tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid 119 (±)-{2-[2-(2-Benzyloxy-acetyl)-5-fluoro-1,2,3,4-tetrahydro- 30.9 isoquinolin-1-yl]-4-chloro-phenoxy}-acetic acid 120 (±)-(4-Chloro-2-{2-[2-(2-chloro-benzyloxy)-acetyl]-5-fluoro- 33.3 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 121 (±)-{4-Chloro-2-[5-fluoro-2-(4-phenyl-butyryl)-1,2,3,4-tetrahydro- 52.3 isoquinolin-1-yl]-phenoxy}-acetic acid 122 (±)-{4-Chloro-2-[5-fluoro-2-(3-phenyl-propynoyl)-1,2,3,4- 196 tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid 123 (±)-{4-Fluoro-2-[2-(3-phenyl-propionyl)-1,2,3,4-tetrahydro- 152 isoquinolin-1-yl]-phenoxy}-acetic acid 124 (±)-[4-Fluoro-2-(2-phenylacetyl-1,2,3,4-tetrahydro-isoquinolin-1- 417 yl)-phenoxy]-acetic acid 125 (±)-{4-Fluoro-2-[2-(2-phenoxy-acetyl)-1,2,3,4-tetrahydro- 175 isoquinolin-1-yl]-phenoxy}-acetic acid 126 (±)-{2-[2-(2-Benzyloxy-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]- 20 4-fluoro-phenoxy}-acetic acid 127 (±)-{4-Fluoro-2-[2-(4-phenyl-butyryl)-1,2,3,4-tetrahydro- 29 isoquinolin-1-yl]-phenoxy}-acetic acid 128 (±)-(4-Fluoro-2-{2-[3-(2-methoxy-phenyl)-propionyl]-1,2,3,4- 69 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 129 (±)-(4-Fluoro-2-{2-[3-(3-methoxy-phenyl)-propionyl]-1,2,3,4- 280 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 130 (±)-(4-Fluoro-2-{2-[3-(4-methoxy-phenyl)-propionyl]-1,2,3,4- 270 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 131 (±)-(2-{2-[3-(2-Chloro-phenyl)-propionyl]-1,2,3,4-tetrahydro- 48 isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic acid 132 (±)-(2-{2-[3-(3-Chloro-phenyl)-propionyl]-1,2,3,4-tetrahydro- 86 isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic acid 133 (±)-(2-{2-[3-(4-Chloro-phenyl)-propionyl]-1,2,3,4-tetrahydro- 126 isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic acid 134 (±)-{4-Fluoro-2-[2-(3-o-tolyl-propionyl)-1,2,3,4-tetrahydro- 31 isoquinolin-1-yl]-phenoxy}-acetic acid 135 (±)-{4-Fluoro-2-[2-(2-naphthalen-2-yl-acetyl)-1,2,3,4-tetrahydro- 42.2 isoquinolin-1-yl]-phenoxy}-acetic acid 136 (±)-{4-Fluoro-2-[2-(2-o-tolyloxy-acetyl)-1,2,3,4-tetrahydro- 119 isoquinolin-1-yl]-phenoxy}-acetic acid 137 (±)-(4-Fluoro-2-{2-[2-(1-methyl-1H-indol-3-yl)-acetyl]-1,2,3,4- 314 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 138 (±)-(2-{2-[2-(2-Chloro-phenoxy)-acetyl]-1,2,3,4-tetrahydro- 101 isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic acid 139 (±)-(4-Fluoro-2-{2-[3-(2-fluoro-phenyl)-propionyl]-1,2,3,4- 233 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 140 (±)-{4-Fluoro-2-[2-(2-indan-2-yl-acetyl)-1,2,3,4-tetrahydro- 36.4 isoquinolin-1-yl]-phenoxy}-acetic acid 141 (±)-(4-Fluoro-2-{2-[(E)-3-(2-fluoro-phenyl)-acryloyl]-1,2,3,4- 835 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 142 (±)-{4-Fluoro-2-[2-((E)-3-o-tolyl-acryloyl)-1,2,3,4-tetrahydro- 349 isoquinolin-1-yl]-phenoxy}-acetic acid 143 (±)-{4-Fluoro-2-[2-(5-phenyl-pentanoyl)-1,2,3,4-tetrahydro- 395 isoquinolin-1-yl]-phenoxy}-acetic acid 144 (±)-{4-Fluoro-2-[2-(3-phenoxy-propionyl)-1,2,3,4-tetrahydro- 73.9 isoquinolin-1-yl]-phenoxy}-acetic acid 145 (±)-(4-Fluoro-2-{2-[3-(4-methanesulfonyl-phenyl)-propionyl]- 983 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 146 (±)-{2-[2-(3-2,3-Dihydro-indol-1-yl-propionyl)-1,2,3,4-tetrahydro- 61.3 isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic acid 147 (±)-{4-Fluoro-2-[2-(3-o-tolyloxy-propionyl)-1,2,3,4-tetrahydro- 57.6 isoquinolin-1-yl]-phenoxy}-acetic acid 148 (±)-(4-Fluoro-2-{2-[2-(2-fluoro-phenoxy)-acetyl]-1,2,3,4- 132 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 149 (±)-(4-Fluoro-2-{2-[4-(2-methoxy-phenyl)-butyryl]-1,2,3,4- 42.7 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 150 (±)-(2-{2-[2-(2-Chloro-benzyloxy)-acetyl]-1,2,3,4-tetrahydro- 6.16 isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic acid 151 (±)-(4-Chloro-2-{2-[(trans)-2-(3-chloro-phenyl)- 264 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid (diastereoisomer 1) 152 (±)-(4-Chloro-2-{2-[(trans)-2-(3-chloro-phenyl)- 33.4 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid (diastereoisomer 2) 153 (±)-{4-Chloro-2-[2-((trans)-2-o-tolyl-cyclopropanecarbonyl)- 123 1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid (diastereosiomer 1) 154 (±)-{4-Chloro-2-[2-((trans)-2-o-tolyl-cyclopropanecarbonyl)- 4.83 1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid (diastereosiomer 2) 155 (±)-(4-Chloro-2-{2-[(trans)-2-(2-trifluoromethyl-phenyl)- 166 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid (diatereoisomer 1) 156 (±)-(4-Chloro-2-{2-[(trans)-2-(2-trifluoromethyl-phenyl)- 14.2 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid (diatereoisomer 2) 157 (±)-(4-Chloro-2-{2-[trans-2-(4-chloro-phenyl)- 45.3 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 158 (±)-(4-Chloro-2-{2-[trans-2-(2,4-dichloro-phenyl)- 37.6 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 159 (±)-(4-Chloro-2-{2-[trans-2-(2-methoxy-phenyl)- 21.2 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 160 (±)-(4-Chloro-2-{2-[trans-2-(2-fluoro-phenyl)- 16.4 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 161 (±)-(4-Chloro-2-{2-[3-(3-phenyl-3H-[1,2,3]triazol-4-yl)-propionyl]- 116 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 162 (±)-(4-Chloro-2-{2-[2-(3-phenyl-3H-[1,2,3]triazol-4-ylsulfanyl)- 115 acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 163 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-6-fluoro-3,4-dihydro- 4.21 1H-isoquinoline-2-carboxylic acid benzyl ester 164 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 0.94 isoquinoline-2-carboxylic acid 2-chloro-benzyl ester 165 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H- 5 isoquinoline-2-carboxylic acid 2-chloro-benzyl ester 166 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H- 120 isoquinoline-2-carboxylic acid 2,2-dimethyl-propyl ester 167 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H- 42 isoquinoline-2-carboxylic acid butyl ester 168 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H- 109 isoquinoline-2-carboxylic acid 2-methoxy-phenyl ester 169 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H- 451 isoquinoline-2-carboxylic acid phenyl ester 170 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H- 169 isoquinoline-2-carboxylic acid 2-chloro-phenyl ester 171 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H- 47.7 isoquinoline-2-carboxylic acid isobutyl ester 172 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H- 59.8 isoquinoline-2-carboxylic acid 2-methoxy-ethyl ester 173 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H- 102 isoquinoline-2-carboxylic acid 4-methoxy-phenyl ester 174 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 5.75 isoquinoline-2-carboxylic acid 2-chloro-benzyl ester 175 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5-fluoro-3,4-dihydro- 8.75 1H-isoquinoline-2-carboxylic acid 2-chloro-benzyl ester 176 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 10.4 isoquinoline-2-carboxylic acid 2-(2-chloro-phenyl)-ethyl ester 177 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H- 27.5 isoquinoline-2-carboxylic acid 2-(2-chloro-phenyl)-ethyl ester 178 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H- 687 isoquinoline-2-carboxylic acid 3-chloro-phenyl ester 179 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5-fluoro-3,4-dihydro- 39.5 1H-isoquinoline-2-carboxylic acid 2-(2-chloro-phenyl)-ethyl ester 180 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-4,4-dimethyl-3,4- 151 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 181 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-7-ethanesulfonyl-3,4- 572 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 182 (±)-1-(2-Carboxymethoxy-5-methanesulfonyl-phenyl)-3,4- 308 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 183 (±)-1-(5-Benzenesulfonyl-2-carboxymethoxy-phenyl)-3,4-dihydro- 64 1H-isoquinoline-2-carboxylic acid benzyl ester 184 (±)-1-(2-Carboxymethoxy-5-ethanesulfonyl-phenyl)-3,4-dihydro- 346 1H-isoquinoline-2-carboxylic acid benzyl ester 185 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-5-methanesulfonyl- 78.7 3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 186 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-5-ethanesulfonyl-3,4- 311 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 187 (±)-5-Benzenesulfonyl-1-(2-carboxymethoxy-5-fluoro-phenyl)- 241 3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 188 (±)-1-(2-Carboxymethoxy-5-pyrimidin-5-yl-phenyl)-3,4-dihydro- 89.4 1H-isoquinoline-2-carboxylic acid benzyl ester 189 (±)-1-(4-Carboxymethoxy-4′-fluoro-biphenyl-3-yl)-3,4-dihydro-1H- 23.3 isoquinoline-2-carboxylic acid benzyl ester 190 (±)-(2-{2-[2-(3-Chloro-benzyloxy)-acetyl]-1,2,3,4-tetrahydro- 16.9 isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic acid 191 (±)-(2-{2-[2-(4-Chloro-benzyloxy)-acetyl]-1,2,3,4-tetrahydro- 33.3 isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic acid 192 (±)-(4-Fluoro-2-{2-[2-(2-methyl-benzyloxy)-acetyl]-1,2,3,4- 11.1 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 193 (±)-(4-Fluoro-2-{2-[2-(3-methyl-benzyloxy)-acetyl]-1,2,3,4- 27.7 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 194 (±)-(4-Fluoro-2-{2-[2-(4-methyl-benzyloxy)-acetyl]-1,2,3,4- 90.2 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 195 (±)-(4-Fluoro-2-{2-[2-(3-methoxy-benzyloxy)-acetyl]-1,2,3,4- 36.3 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 196 (±)-(4-Fluoro-2-{2-[2-(4-methoxy-benzyloxy)-acetyl]-1,2,3,4- 146 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 197 (±)-(4-Fluoro-2-{2-[2-(1-methyl-1H-pyrazol-3-ylmethoxy)-acetyl]- 323 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 198 (±)-(4-Fluoro-2-{2-[2-(2-methoxy-benzyloxy)-acetyl]-1,2,3,4- 19 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 199 (±)-[2-(2-Benzylcarbamoyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-4- 54 fluoro-phenoxy]-acetic acid 200 (±)-[4-Fluoro-2-(2-phenethylcarbamoyl-1,2,3,4-tetrahydro- 31 isoquinolin-1-yl)-phenoxy]-acetic acid 201 (±)-{4-Fluoro-2-[2-(2-methoxy-benzylcarbamoyl)-1,2,3,4- 21 tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid 202 (±)-{4-Chloro-2-[2-(2-methoxy-benzylcarbamoyl)-1,2,3,4- 7.29 tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid 203 (±)-{2-[2-(2-Chloro-benzylcarbamoyl)-1,2,3,4-tetrahydro- 27.9 isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic acid 204 (±)-(2-{2-[2-(2-Chloro-phenyl)-ethylcarbamoyl]-1,2,3,4-tetrahydro- 83 isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic acid 205 (±)-{2-[2-(2-Benzenesulfonylamino-acetyl)-1,2,3,4-tetrahydro- 928 isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic acid 206 (±)-(2-{2-[2-(3,5-Dimethyl-isoxazole-4-sulfonylamino)-acetyl]- 819 1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic acid 207 (±)-(4-Fluoro-2-{2-[2-(3-fluoro-benzenesulfonylamino)-acetyl]- 347 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 208 (±)-(4-Fluoro-2-{2-[2-(2-fluoro-benzenesulfonylamino)-acetyl]- 983 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 209 (±)-(2-{2-[2-(3,4-Difluoro-benzenesulfonylamino)-acetyl]-1,2,3,4- 644 tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic acid 210 (±)-(2-{2-[2-(N-Benzenesulfonyl-N-methyl-amino)-acetyl]-1,2,3,4- 423 tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic acid 211 (±)-[4-Fluoro-2-(2-{2-[N-(3-fluoro-benzenesulfonyl)-N-methyl- 261 amino]-acetyl}-1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]- acetic acid 212 (±)-[2-(2-{2-[N-(3,4-Difluoro-benzenesulfonyl)-N-methyl-amino]- 920 acetyl}-1,2,3,4-tetrahydro-isoquinolin-1-yl)-4-fluoro-phenoxy]- acetic acid 213 (±)-1-(5-Carbamoyl-2-carboxymethoxy-phenyl)-3,4-dihydro-1H- 344 isoquinoline-2-carboxylic acid benzyl ester 214 (±)-1-[2-Carboxymethoxy-5-(5-thioxo-4,5-dihydro- 147 [1,2,4]oxadiazol-3-yl)-phenyl]-3,4-dihydro-1H-isoquinoline-2- carboxylic acid benzyl ester 215 (±)-1-(2-Carboxymethoxy-4-fluoro-phenyl)-3,4-dihydro-1H- 27 isoquinoline-2-carboxylic acid benzyl ester 216 (±)-1-(2-Carboxymethoxy-6-fluoro-phenyl)-3,4-dihydro-1H- 182 isoquinoline-2-carboxylic acid benzyl ester 217 (±)-1-[2-(3-Carboxy-propoxy)-5-fluoro-phenyl]-3,4-dihydro-1H- 110 isoquinoline-2-carboxylic acid benzyl ester 218 (±)-{4-Cyano-2-[2-(trans-2-phenyl-cyclopropanecarbonyl)- 13.4 1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid 219 (±)-1-(2-Carboxymethoxy-5-cyano-phenyl)-3,4-dihydro-1H- 4.72 isoquinoline-2-carboxylic acid benzyl ester 220 (R)-1-[2-(1-Carboxy-ethoxy)-5-chloro-phenyl]-3,4-dihydro-1H- 21 isoquinoline-2-carboxylic acid benzyl ester 221 (S)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H- 2.91 isoquinoline-2-carboxylic acid benzyl ester 222 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-5- 141 methanesulfonylamino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 223 (±)-1-(2-Carboxymethoxy-5-[1,2,3]triazol-1-yl-phenyl)-3,4- 7.01 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 224 (±)-1-(2-Carboxymethoxy-5-[1,2,3]triazol-2-yl-phenyl)-3,4- 12.7 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 225 (±)-{4-Chloro-2-[2-(2-methoxy-benzylthiocarbamoyl)-1,2,3,4- 76.5 tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid 226 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 5.23 1H-isoquinoline-2-carboxylic acid benzyl ester 227 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 7.21 isoquinoline-2-carboxylic acid 2-bromo-benzyl ester 228 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 71.3 isoquinoline-2-carboxylic acid tert-butyl ester 229 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 4.95 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 230 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-1,3-dihydro-isoindole- 12.8 2-carboxylic acid benzyl ester 231 1-(2-Carboxymethoxy-5-chloro-phenyl)-1,3-dihydro-isoindole-2- 2.65 carboxylic acid benzyl ester (enantiomer 1) 232 {4-Chloro-2-[(S)-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)- 1.39 1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid 233 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 4.55 isoquinoline-2-carboxylic acid 2-methoxy-benzyl ester 234 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 3.61 isoquinoline-2-carboxylic acid 2-fluoro-benzyl ester 235 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 5.62 isoquinoline-2-carboxylic acid 2-methyl-benzyl ester 236 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 5.59 isoquinoline-2-carboxylic acid 2-trifluoromethyl-benzyl ester 237 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 4.02 isoquinoline-2-carboxylic acid 3-methoxy-benzyl ester 238 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 12.6 isoquinoline-2-carboxylic acid 3-fluoro-benzyl ester 239 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 17.7 isoquinoline-2-carboxylic acid 3-methyl-benzyl ester 240 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 18.6 isoquinoline-2-carboxylic acid 3-trifluoromethyl-benzyl ester 241 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 0.96 isoquinoline-2-carboxylic acid 2,4-dichloro-benzyl ester 242 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 1.07 isoquinoline-2-carboxylic acid 2,3-dichloro-benzyl ester 243 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 6.48 isoquinoline-2-carboxylic acid 2,6-dichloro-benzyl ester 244 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 7.67 isoquinoline-2-carboxylic acid 2,6-dimethoxy-benzyl ester 245 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 2.87 isoquinoline-2-carboxylic acid 2,4-dimethyl-benzyl ester 246 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 3.43 isoquinoline-2-carboxylic acid 2,3-dimethyl-benzyl ester 247 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 17.3 isoquinoline-2-carboxylic acid 2,6-dimethyl-benzyl ester 248 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 3.3 isoquinoline-2-carboxylic acid 2,4-difluoro-benzyl ester 249 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 3.86 isoquinoline-2-carboxylic acid 2,3-difluoro-benzyl ester 250 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 6.84 isoquinoline-2-carboxylic acid 2,6-difluoro-benzyl ester 251 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 12.3 isoquinoline-2-carboxylic acid 2,4,6-trimethyl-benzyl ester 252 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 3.98 isoquinoline-2-carboxylic acid 2-chloro-6-fluoro-benzyl ester 253 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 6.52 isoquinoline-2-carboxylic acid 2,5-dichloro-benzyl ester 254 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 16 isoquinoline-2-carboxylic acid 2,4-dimethoxy-benzyl ester 255 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 4.9 isoquinoline-2-carboxylic acid 2,3-dimethoxy-benzyl ester 256 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 14.1 isoquinoline-2-carboxylic acid 2,6-dimethyl-pyridin-3-ylmethyl ester 257 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 5.72 isoquinoline-2-carboxylic acid 3-cyano-benzyl ester 258 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 7.54 isoquinoline-2-carboxylic acid 2,5-difluoro-benzyl ester 259 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 5.29 isoquinoline-2-carboxylic acid 5-chloro-2-fluoro-benzyl ester 260 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 15.1 isoquinoline-2-carboxylic acid 2-chloro-5-fluoro-benzyl ester 261 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 97.1 isoquinoline-2-carboxylic acid (S)-1-phenyl-ethyl ester 262 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 9.43 isoquinoline-2-carboxylic acid cyclohexylmethyl ester 263 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 7.91 isoquinoline-2-carboxylic acid 1-methyl-1H-pyrazol-3-ylmethyl ester 264 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 13.1 isoquinoline-2-carboxylic acid cyclopentylmethyl ester 265 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 37.6 isoquinoline-2-carboxylic acid isobutyl ester 266 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 24.5 isoquinoline-2-carboxylic acid butyl ester 267 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 21.2 isoquinoline-2-carboxylic acid 2-methoxy-ethyl ester 268 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 27.7 isoquinoline-2-carboxylic acid cyclopropylmethyl ester 269 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 4.95 isoquinoline-2-carboxylic acid 3,5-dimethyl-pyrazol-1-ylmethyl ester 270 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 8.31 isoquinoline-2-carboxylic acid 5-methyl-isoxazol-3-ylmethyl ester 271 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 12 isoquinoline-2-carboxylic acid 1,5-dimethyl-1H-pyrazol-3-ylmethyl ester 272 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 17.1 isoquinoline-2-carboxylic acid 4-chloro-benzyl ester 273 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 2.04 isoquinoline-2-carboxylic acid thiazol-2-ylmethyl ester 274 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 2.42 isoquinoline-2-carboxylic acid 2-(4-methyl-thiazol-5-yl)-ethyl ester 275 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 5.01 isoquinoline-2-carboxylic acid 5-methyl-thiazol-2-ylmethyl ester 276 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 1.82 isoquinoline-2-carboxylic acid 4-methyl-thiazol-2-ylmethyl ester 277 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 0.77 isoquinoline-2-carboxylic acid 2-methyl-thiazol-5-ylmethyl ester 278 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 1.28 isoquinoline-2-carboxylic acid 2-methyl-thiazol-4-ylmethyl ester 279 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 0.87 isoquinoline-2-carboxylic acid 3-methyl-isoxazol-5-ylmethyl ester 280 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 0.35 isoquinoline-2-carboxylic acid 4-methyl-isoxazol-3-ylmethyl ester 281 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 4.8 isoquinoline-2-carboxylic acid 3,5-dimethyl-isoxazol-4-ylmethyl ester 282 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 3.96 isoquinoline-2-carboxylic acid pyrazin-2-ylmethyl ester 283 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 7.56 isoquinoline-2-carboxylic acid pyrimidin-4-ylmethyl ester 284 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 0.86 isoquinoline-2-carboxylic acid pyrimidin-5-ylmethyl ester 285 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 3.17 isoquinoline-2-carboxylic acid phenethyl ester 286 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 2.67 isoquinoline-2-carboxylic acid 2-(3-fluoro-phenyl)-ethyl ester 287 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 0.20 isoquinoline-2-carboxylic acid 2-methyl-2H-pyrazol-3-ylmethyl ester 288 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 0.41 isoquinoline-2-carboxylic acid 2,5-dimethyl-2H-pyrazol-3-ylmethyl ester 289 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 2.94 isoquinoline-2-carboxylic acid 2-(2-ethyl-5-methyl-2H-pyrazol-3- yl)-ethyl ester 290 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 0.48 isoquinoline-2-carboxylic acid 3-methyl-3H-imidazol-4-ylmethyl ester 291 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 8.92 isoquinoline-2-carboxylic acid 2-(3,5-dimethyl-pyrazol-1-yl)-ethyl ester 292 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 2.08 isoquinoline-2-carboxylic acid 4-methyl-pyrazol-1-ylmethyl ester 293 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 98.1 isoquinoline-2-carboxylic acid 2-(2-methyl-benzoimidazol-1-yl)- ethyl ester 294 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 1.94 isoquinoline-2-carboxylic acid benzothiazol-2-ylmethyl ester 295 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 7.41 isoquinoline-2-carboxylic acid benzooxazol-2-ylmethyl ester 296 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 1.72 isoquinoline-2-carboxylic acid 1-methyl-1H-indazol-3-ylmethyl ester 297 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 1.06 isoquinoline-2-carboxylic acid indazol-1-ylmethyl ester 298 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 2.49 isoquinoline-2-carboxylic acid benzo[d]isoxazol-3-ylmethyl ester 299 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 6.83 dihydro-1H-isoquinoline-2-carboxylic acid thiazol-2-ylmethyl ester 300 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 6.39 dihydro-1H-isoquinoline-2-carboxylic acid 2-(4-methyl-thiazol-5- yl)-ethyl ester 301 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 4.55 dihydro-1H-isoquinoline-2-carboxylic acid 5-methyl-thiazol-2- ylmethyl ester 302 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 5.7 dihydro-1H-isoquinoline-2-carboxylic acid 4-methyl-thiazol-2- ylmethyl ester 303 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 5.05 dihydro-1H-isoquinoline-2-carboxylic acid 2-methyl-thiazol-5- ylmethyl ester 304 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 5.39 dihydro-1H-isoquinoline-2-carboxylic acid 2-methyl-thiazol-4- ylmethyl ester 305 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 2.13 dihydro-1H-isoquinoline-2-carboxylic acid 3-methyl-isoxazol-5- ylmethyl ester 306 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 3.12 dihydro-1H-isoquinoline-2-carboxylic acid 4-methyl-isoxazol-3- ylmethyl ester 307 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 3.34 dihydro-1H-isoquinoline-2-carboxylic acid 3,5-dimethyl-isoxazol- 4-ylmethyl ester 308 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 1.69 dihydro-1H-isoquinoline-2-carboxylic acid pyrazin-2-ylmethyl ester 309 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 4.77 dihydro-1H-isoquinoline-2-carboxylic acid pyrimidin-4-ylmethyl ester 310 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 5.14 dihydro-1H-isoquinoline-2-carboxylic acid phenethyl ester 311 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 11 dihydro-1H-isoquinoline-2-carboxylic acid 2-(3-fluoro-phenyl)- ethyl ester 312 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 4.65 dihydro-1H-isoquinoline-2-carboxylic acid 2-methyl-2H-pyrazol-3- ylmethyl ester 313 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 2.37 dihydro-1H-isoquinoline-2-carboxylic acid 2,5-dimethyl-2H- pyrazol-3-ylmethyl ester 314 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 9.8 dihydro-1H-isoquinoline-2-carboxylic acid 2-(2-ethyl-5-methyl- 2H-pyrazol-3-yl)-ethyl ester 315 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 2.82 dihydro-1H-isoquinoline-2-carboxylic acid 3-methyl-3H-imidazol- 4-ylmethyl ester 316 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 5.07 dihydro-1H-isoquinoline-2-carboxylic acid 2-(3,5-dimethyl- pyrazol-1-yl)-ethyl ester 317 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 14.7 dihydro-1H-isoquinoline-2-carboxylic acid 4-methyl-pyrazol-1- ylmethyl ester 318 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 138 dihydro-1H-isoquinoline-2-carboxylic acid 2-(2-methyl- benzoimidazol-1-yl)-ethyl ester 319 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 1.44 dihydro-1H-isoquinoline-2-carboxylic acid benzothiazol-2- ylmethyl ester 320 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 0.52 dihydro-1H-isoquinoline-2-carboxylic acid benzooxazol-2- ylmethyl ester 321 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 1.84 dihydro-1H-isoquinoline-2-carboxylic acid 1-methyl-1H-indazol-3- ylmethyl ester 322 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 0.53 dihydro-1H-isoquinoline-2-carboxylic acid indazol-1-ylmethyl ester 323 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 1.2 dihydro-1H-isoquinoline-2-carboxylic acid benzo[d]isoxazol-3- ylmethyl ester 324 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 6.26 1H-isoquinoline-2-carboxylic acid thiazol-2-ylmethyl ester 325 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 21.3 1H-isoquinoline-2-carboxylic acid 2-(4-methyl-thiazol-5-yl)-ethyl ester 326 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 8.67 1H-isoquinoline-2-carboxylic acid 5-methyl-thiazol-2-ylmethyl ester 327 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 3.38 1H-isoquinoline-2-carboxylic acid 4-methyl-thiazol-2-ylmethyl ester 328 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 3.2 1H-isoquinoline-2-carboxylic acid 2-methyl-thiazol-5-ylmethyl ester 329 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 5.9 1H-isoquinoline-2-carboxylic acid 2-methyl-thiazol-4-ylmethyl ester 330 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 10.6 1H-isoquinoline-2-carboxylic acid 3-methyl-isoxazol-5-ylmethyl ester 331 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 7.29 1H-isoquinoline-2-carboxylic acid 4-methyl-isoxazol-3-ylmethyl ester 332 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 7.65 1H-isoquinoline-2-carboxylic acid pyrazin-2-ylmethyl ester 333 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 45.7 1H-isoquinoline-2-carboxylic acid pyrimidin-4-ylmethyl ester 334 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 4.95 1H-isoquinoline-2-carboxylic acid pyrimidin-5-ylmethyl ester 335 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 13.3 1H-isoquinoline-2-carboxylic acid phenethyl ester 336 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 11.5 1H-isoquinoline-2-carboxylic acid 2-(3-fluoro-phenyl)-ethyl ester 337 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 3.61 1H-isoquinoline-2-carboxylic acid 2-methyl-2H-pyrazol-3-ylmethyl ester 338 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 3.13 1H-isoquinoline-2-carboxylic acid 2,5-dimethyl-2H-pyrazol-3- ylmethyl ester 339 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 11.5 1H-isoquinoline-2-carboxylic acid 2-(2-ethyl-5-methyl-2H-pyrazol- 3-yl)-ethyl ester 340 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 5.17 1H-isoquinoline-2-carboxylic acid 3-methyl-3H-imidazol-4- ylmethyl ester 341 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 11.1 1H-isoquinoline-2-carboxylic acid 2-(3,5-dimethyl-pyrazol-1-yl)- ethyl ester 342 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 17.9 1H-isoquinoline-2-carboxylic acid 4-methyl-pyrazol-1-ylmethyl ester 343 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 266 1H-isoquinoline-2-carboxylic acid 2-(2-methyl-benzoimidazol-1- yl)-ethyl ester 344 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 37.8 1H-isoquinoline-2-carboxylic acid benzothiazol-2-ylmethyl ester 345 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 12.4 1H-isoquinoline-2-carboxylic acid benzooxazol-2-ylmethyl ester 346 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 1.16 1H-isoquinoline-2-carboxylic acid 1-methyl-1H-indazol-3-ylmethyl ester 347 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 0.87 1H-isoquinoline-2-carboxylic acid indazol-1-ylmethyl ester 348 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 0.40 1H-isoquinoline-2-carboxylic acid benzo[d]isoxazol-3-ylmethyl ester 349 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 8.99 dihydro-1H-isoquinoline-2-carboxylic acid 2-fluoro-benzyl ester 350 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 3.38 dihydro-1H-isoquinoline-2-carboxylic acid 3-fluoro-benzyl ester 351 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4- 3.27 dihydro-1H-isoquinoline-2-carboxylic acid 2,3-difluoro-benzyl ester 352 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 1.87 1H-isoquinoline-2-carboxylic acid 2-fluoro-benzyl ester 353 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 2.79 1H-isoquinoline-2-carboxylic acid 3-fluoro-benzyl ester 354 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 7.72 1H-isoquinoline-2-carboxylic acid 2,3-difluoro-benzyl ester 355 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 2.01 isoquinoline-2-carboxylic acid 3-fluoro-benzyl ester 356 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 3.58 isoquinoline-2-carboxylic acid 2-methoxy-benzyl ester 357 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 1.23 isoquinoline-2-carboxylic acid 2-fluoro-benzyl ester 358 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5-fluoro-3,4-dihydro- 2.84 1H-isoquinoline-2-carboxylic acid 3-fluoro-benzyl ester 359 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5-fluoro-3,4-dihydro- 1.79 1H-isoquinoline-2-carboxylic acid 2-fluoro-benzyl ester 360 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 18.8 isoquinoline-2-carboxylic acid 4-methyl-benzyl ester 361 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 22.8 isoquinoline-2-carboxylic acid 4-methoxy-benzyl ester 362 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 14.3 isoquinoline-2-carboxylic acid 4-fluoro-benzyl ester 363 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 34.1 isoquinoline-2-carboxylic acid 4-trifluoromethyl-benzyl ester 364 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H- 16.5 isoquinoline-2-carboxylic acid 3-chloro-benzyl ester 365 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-7-fluoro-3,4-dihydro- 37.8 1H-isoquinoline-2-carboxylic acid benzyl ester 366 (±)-1-(2-Carboxymethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2- 41.5 carboxylic acid benzyl ester 367 (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro- 4.89 1H-isoquinoline-2-carboxylic acid benzyl ester 368 (±)-(4-Chloro-2-{2-[3-(5-fluoro-3-methyl-indol-1-yl)-propionyl]- 20.7 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 369 (±)-{4-Chloro-2-[2-(3-pyrrolo[2,3-b]pyridin-1-yl-propionyl)-1,2,3,4- 195 tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid 370 (±)-(4-Chloro-2-{2-[3-(6-trifluoromethyl-indol-1-yl)-propionyl]- 80.6 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 371 (±)-(4-Chloro-2-{2-[3-(5-cyano-indol-1-yl)-propionyl]-1,2,3,4- 53.1 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 372 (±)-{4-Chloro-2-[2-(3-pyrrolo[2,3-c]pyridin-1-yl-propionyl)-1,2,3,4- 596 tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid 373 (±)-(4-Chloro-2-{2-[3-(6-methoxy-pyrrolo[3,2-c]pyridin-1-yl)- 433 propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 374 (±)-(4-Chloro-2-{2-[3-(6-methoxy-pyrrolo[2,3-b]pyridin-1-yl)- 12.3 propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 375 (±)-(4-Chloro-2-{2-[3-(5-chloro-6-methoxy-indol-1-yl)-propionyl]- 81.8 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 376 (±)-(4-Chloro-2-{2-[3-(4,6-dimethoxy-pyrrolo[2,3-b]pyridin-1-yl)- 32.5 propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 377 (±)-(4-Chloro-2-{2-[3-(4,6-dimethoxy-indol-1-yl)-propionyl]- 9.71 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 378 (±)-{4-Chloro-2-[2-(3-indol-1-yl-propionyl)-1,2,3,4-tetrahydro- 11.6 isoquinolin-1-yl]-phenoxy}-acetic acid 379 (±)-(4-Chloro-2-{2-[3-(5-fluoro-indol-1-yl)-propionyl]-1,2,3,4- 16.8 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 380 (±)-(4-Chloro-2-{2-[3-(7-chloro-indol-1-yl)-propionyl]-1,2,3,4- 24.3 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 381 (±)-{4-Chloro-2-[2-(3-pyrrolo[3,2-b]pyridin-1-yl-propionyl)-1,2,3,4- 31.6 tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid 382 (±)-(4-Chloro-2-{2-[3-(4-methoxy-indol-1-yl)-propionyl]-1,2,3,4- 20.7 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 383 (±)-(4-Chloro-2-{2-[3-(3-chloro-indazol-1-yl)-propionyl]-1,2,3,4- 8.5 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 384 (±)-(4-Chloro-2-{2-[3-(6-methyl-indol-1-yl)-propionyl]-1,2,3,4- 14.8 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 385 (±)-(4-Chloro-2-{2-[3-(5-chloro-indol-1-yl)-propionyl]-1,2,3,4- 51.2 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 386 (±)-(4-Chloro-2-{2-[3-(6-chloro-indol-1-yl)-propionyl]-1,2,3,4- 11.6 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 387 (±)-(4-Chloro-2-{2-[3-(4-fluoro-indol-1-yl)-propionyl]-1,2,3,4- 36.7 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 388 (±)-(4-Chloro-2-{2-[3-(6-fluoro-indol-1-yl)-propionyl]-1,2,3,4- 25.7 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 389 (±)-(4-Chloro-2-{2-[3-(2,3-dimethyl-indol-1-yl)-propionyl]-1,2,3,4- 70.4 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 390 (±)-(4-Chloro-2-{2-[3-(6-methoxy-indol-1-yl)-propionyl]-1,2,3,4- 7.52 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 391 (4-Chloro-2-{(S)-6-fluoro-2-[3-(4-fluoro-3-methyl-indazol-1-yl)- 158 propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 392 (4-Chloro-2-{(S)-6-fluoro-2-[3-(7-fluoro-3-methyl-indazol-1-yl)- 273 propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 393 (4-Chloro-2-{(S)-6-fluoro-2-[3-(6-fluoro-3-methyl-indazol-1-yl)- 154 propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 394 (4-Chloro-2-{(S)-2-[3-(6-chloro-3-methyl-indazol-1-yl)-propionyl]- 185 6-fluoro-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 395 (4-Chloro-2-{(S)-6-fluoro-2-[3-(5-fluoro-indazol-1-yl)-propionyl]- 28.4 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 396 (4-Chloro-2-{(S)-2-[3-(5-chloro-indazol-1-yl)-propionyl]-6-fluoro- 152 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 397 (4-Chloro-2-{(S)-6-fluoro-2-[3-(3-methyl-indazol-1-yl)-propionyl]- 32.1 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 398 (4-Chloro-2-{(S)-6-fluoro-2-[3-(6-fluoro-indazol-1-yl)-propionyl]- 64.7 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 399 (4-Chloro-2-{(S)-6-fluoro-2-[3-(4-fluoro-indazol-1-yl)-propionyl]- 144 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 400 (4-Chloro-2-{(S)-2-[3-(7-chloro-indazol-1-yl)-propionyl]-6-fluoro- 678 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 401 (4-Chloro-2-{(S)-2-[3-(6-chloro-indazol-1-yl)-propionyl]-6-fluoro- 46.9 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 402 (4-Chloro-2-{(S)-2-[3-(4-chloro-indazol-1-yl)-propionyl]-6-fluoro- 170 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 403 (4-Chloro-2-{(S)-6-fluoro-2-[3-(7-fluoro-indazol-1-yl)-propionyl]- 79.1 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 404 (±)-(4-Chloro-2-{2-[3-(3-chloro-pyrrolo[2,3-b]pyrazin-5-yl)- 42.6 propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 405 (±)-(4-Chloro-2-{2-[3-(2-trifluoromethyl-indol-1-yl)-propionyl]- 451 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 406 (±)-(4-Chloro-2-{2-[2-(2-methoxy-phenoxy)-acetyl]-1,2,3,4- 26.8 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 407 (±)-(4-Chloro-2-{2-[2-(4-fluoro-phenoxy)-acetyl]-1,2,3,4- 34.9 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 408 (±)-(4-Chloro-2-{2-[3-(6-methyl-pyridin-2-yl)-propionyl]-1,2,3,4- 177 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 409 (±)-{4-Chloro-2-[2-(2-phenoxy-acetyl)-1,2,3,4-tetrahydro- 74 isoquinolin-1-yl]-phenoxy}-acetic acid 410 (±)-(4-Chloro-2-{2-[2-(2-fluoro-phenoxy)-acetyl]-1,2,3,4- 70.7 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 411 (±)-(4-Chloro-2-{2-[2-(quinolin-8-yloxy)-acetyl]-1,2,3,4-tetrahydro- 25.7 isoquinolin-1-yl}-phenoxy)-acetic acid 412 (±)-(4-Chloro-2-{2-[2-(4-chloro-phenoxy)-acetyl]-1,2,3,4- 40.2 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 413 (±)-(4-Chloro-2-{2-[2-(3-chloro-phenoxy)-acetyl]-1,2,3,4- 70.5 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 414 (±)-{4-Chloro-2-[2-(2-p-tolyloxy-acetyl)-1,2,3,4-tetrahydro- 126 isoquinolin-1-yl]-phenoxy}-acetic acid 415 (±)-(4-Chloro-2-{2-[2-(4-methoxy-phenoxy)-acetyl]-1,2,3,4- 210 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 416 (±)-(4-Chloro-2-{2-[2-(pyridin-3-yloxy)-acetyl]-1,2,3,4-tetrahydro- 215 isoquinolin-1-yl}-phenoxy)-acetic acid 417 (±)-(4-Chloro-2-{2-[trans-2-(4-methoxy-phenyl)- 187 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 418 (±)-(4-Chloro-2-{2-[trans-2-(4-fluoro-phenyl)- 16.3 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 419 (±)-(4-Chloro-2-{2-[trans-2-(4-trifluoromethyl-phenyl)- 958 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 420 (±)-{4-Chloro-2-[2-(trans-2-p-tolyl-cyclopropanecarbonyl)-1,2,3,4- 103 tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid 421 (±)-(4-Chloro-2-{2-[trans-2-(3-chloro-phenyl)- 24 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 422 (±)-{4-Chloro-2-[2-(trans-2-o-tolyl-cyclopropanecarbonyl)-1,2,3,4- 5.58 tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid 423 (±)-(4-Chloro-2-{2-[trans-2-(2-trifluoromethyl-phenyl)- 6.62 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 424 (±)-(4-Chloro-2-{2-[trans-2-(3-fluoro-phenyl)- 12 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 425 (±)-(4-Chloro-2-{2-[trans-2-(3-methoxy-phenyl)- 30.6 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 426 (±)-(4-Chloro-2-{2-[trans-2-(3-trifluoromethyl-phenyl)- 93.8 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 427 (±)-{4-Chloro-2-[2-(trans-2-m-tolyl-cyclopropanecarbonyl)- 46.6 1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid 428 (±)-{4-Chloro-2-[6-fluoro-2-(trans-2-phenyl- 1.33 cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]- phenoxy}-acetic acid 429 (±)-(4-Chloro-2-{6-fluoro-2-[trans-2-(2-trifluoromethyl-phenyl)- 2.21 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 430 (±)-(4-Chloro-2-{2-[2-(trans-2-chloro-phenyl)- 9.37 cyclopropanecarbonyl]-6-fluoro-1,2,3,4-tetrahydro-isoquinolin-1- yl}-phenoxy)-acetic acid 431 (±)-{4-Chloro-2-[6-fluoro-2-(trans-2-o-tolyl- 3.56 cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]- phenoxy}-acetic acid 432 (±)-(4-Chloro-2-{2-[2-(2,6-dimethyl-pyridin-3-yloxy)-acetyl]-6- 40.6 fluoro-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 433 (±)-(4-Chloro-2-{6-fluoro-2-[3-(5-methoxy-1H-indol-3-yl)- 90.1 propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 434 (±)-(4-Chloro-2-{6-fluoro-2-[3-(1-methyl-1H-indol-3-yl)-propionyl]- 33.3 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 435 (±)-{4-Chloro-2-[6-fluoro-2-(3-o-tolyl-propionyl)-1,2,3,4- 46.5 tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid 436 (±)-(4-Chloro-2-{6-fluoro-2-[4-(2-fluoro-phenyl)-butyryl]-1,2,3,4- 5.73 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 437 (±)-(4-Chloro-2-{2-[2-(2-chloro-benzyloxy)-acetyl]-6-fluoro- 5.23 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 438 (±)-(4-Chloro-2-{6-fluoro-2-[3-(4-fluoro-phenoxy)-propionyl]- 91.1 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 439 (±)-(4-Chloro-2-{2-[2-(methyl-phenyl-amino)-acetyl]-1,2,3,4- 379 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 440 (±)-(4-Chloro-2-{2-[4-(2-oxo-pyrrolidin-1-yl)-butyryl]-1,2,3,4- 55.7 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 441 (±)-{4-Chloro-2-[2-(3-2,3-dihydro-indol-1-yl-propionyl)-1,2,3,4- 12.7 tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid 442 (±)-(4-Chloro-2-{2-[3-(6-chloro-3-oxo-2,3-dihydro- 347 benzo[1,4]oxazin-4-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin- 1-yl}-phenoxy)-acetic acid 443 (±)-{4-Chloro-2-[2-(2-phenylamino-acetyl)-1,2,3,4-tetrahydro- 855 isoquinolin-1-yl]-phenoxy}-acetic acid 444 (±)-{4-Chloro-2-[2-(2-1,3-dihydro-isoindol-2-yl-acetyl)-1,2,3,4- 667 tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid 445 (±)-(4-Chloro-2-{2-[3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionyl]- 130 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 446 (±)-(4-Chloro-2-{2-[3-(2-methyl-indol-1-yl)-propionyl]-1,2,3,4- 175 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 447 (±)-(4-Chloro-2-{2-[3-(3-methyl-indol-1-yl)-propionyl]-1,2,3,4- 13.9 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 448 (±)-{4-Chloro-2-[2-(3-indazol-1-yl-propionyl)-1,2,3,4-tetrahydro- 35.4 isoquinolin-1-yl]-phenoxy}-acetic acid 449 (±)-{4-Chloro-2-[2-(3-3,4-dihydro-2H-quinolin-1-yl-propionyl)- 26.1 1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid 450 (±)-{4-Chloro-2-[2-(3-isobutoxy-propionyl)-1,2,3,4-tetrahydro- 403 isoquinolin-1-yl]-phenoxy}-acetic acid 451 (±)-{2-[2-(3-Benzoimidazol-1-yl-propionyl)-1,2,3,4-tetrahydro- 64.1 isoquinolin-1-yl]-4-chloro-phenoxy}-acetic acid 452 (±)-(4-Chloro-2-{2-[3-(4-methyl-2-oxo-thiazol-3-yl)-propionyl]- 500 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 453 (±)-(4-Chloro-2-{2-[3-(2-oxo-thiazolidin-3-yl)-propionyl]-1,2,3,4- 312 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 454 (±)-(4-Chloro-2-{2-[3-(2,4-dimethyl-phenyl)-propionyl]-1,2,3,4- 69.6 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 455 (±)-(4-Chloro-2-{2-[3-(2,6-dimethyl-pyridin-3-yl)-propionyl]- 200 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 456 (±)-(4-Chloro-2-{2-[2-(2,4-dimethyl-phenoxy)-acetyl]-1,2,3,4- 43.6 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 457 (±)-(4-Chloro-2-{2-[3-(1,2-dimethyl-1H-indol-3-yl)-propionyl]- 60.8 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 458 (±)-(4-Chloro-2-{2-[3-(5-methoxy-1-methyl-1H-indol-3-yl)- 47.5 propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 459 (±)-(4-Chloro-2-{2-[3-(5-methoxy-indol-1-yl)-propionyl]-1,2,3,4- 160 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 460 {4-Chloro-2-[(S)-2-(trans-2-ethyl-cyclopropanecarbonyl)-1,2,3,4- 67.8 tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid 461 {4-Chloro-2-[(S)-2-(trans-2-ethoxy-cyclopropanecarbonyl)- 185 1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid 462 {4-Chloro-2-[(S)-2-(trans-2-methyl-cyclopropanecarbonyl)- 80.9 1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid 463 (±)-{4-Chloro-2-[2-(3-1H-indol-3-yl-propionyl)-1,2,3,4-tetrahydro- 12.1 isoquinolin-1-yl]-phenoxy}-acetic acid 464 {4-Chloro-2-[(S)-2-(trans-2-isopropyl-cyclopropanecarbonyl)- 789 1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid (diastereoisomer 1) 465 {4-Chloro-2-[(S)-2-(trans-2-isopropyl-cyclopropanecarbonyl)- 53.5 1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid (diastereoisomer 2) 466 (±)-{4-Chloro-2-[2-(2,2-dimethyl-cyclopropanecarbonyl)-1,2,3,4- 24.2 tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid 467 (±)-(4-Chloro-2-{2-[2-(2,4-dimethyl-thiazol-5-yl)- 396 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 468 (±)-(4-Chloro-2-{2-[2-(6-methyl-pyridin-3-yloxy)-acetyl]-1,2,3,4- 759 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 469 (±)-(4-Chloro-2-{2-[2-(2-methyl-pyridin-3-yloxy)-acetyl]-1,2,3,4- 132 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 470 (±)-(4-Chloro-2-{2-[2-(5-chloro-pyridin-3-yloxy)-acetyl]-1,2,3,4- 152 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 471 (±)-(4-Chloro-2-{2-[2-(2-chloro-pyridin-3-yloxy)-acetyl]-1,2,3,4- 87.6 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 472 (±)-(4-Chloro-2-{2-[2-(6-chloro-pyridin-3-yloxy)-acetyl]-1,2,3,4- 109 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 473 (±)-(4-Chloro-2-{2-[2-(2,6-dichloro-pyridin-4-yloxy)-acetyl]- 650 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 474 (±)-(4-Chloro-2-{2-[2-(5-methyl-pyridin-3-yloxy)-acetyl]-1,2,3,4- 198 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 475 (±)-[4-Chloro-2-(2-{2-[2-(2-hydroxy-ethoxy)-pyridin-3-yloxy]- 337 acetyl}-1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid 476 (±)-(4-Chloro-2-{2-[2-(2,6-dimethoxy-pyridin-3-yloxy)-acetyl]- 164 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 477 (±)-(4-Chloro-2-{2-[2-(5-methoxy-pyridin-3-yloxy)-acetyl]-1,2,3,4- 288 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 478 (±)-(4-Chloro-2-{2-[2-(5-fluoro-pyridin-3-yloxy)-acetyl]-1,2,3,4- 232 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 479 (±)-(2-{2-[2-(2-Carbamoyl-pyridin-3-yloxy)-acetyl]-1,2,3,4- 199 tetrahydro-isoquinolin-1-yl}-4-chloro-phenoxy)-acetic acid 480 (±)-(4-Chloro-2-{2-[2-(2-cyano-pyridin-3-yloxy)-acetyl]-1,2,3,4- 104 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 481 (±)-(4-Chloro-2-{2-[2-(6-trifluoromethyl-pyridin-3-yloxy)-acetyl]- 143 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 482 (±)-(4-Chloro-2-{2-[2-(2-fluoro-pyridin-3-yloxy)-acetyl]-1,2,3,4- 199 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 483 (±)-(4-Chloro-2-{2-[2-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yloxy)- 470 acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 484 (±)-(4-Chloro-2-{2-[2-(2-methoxy-5-methyl-pyridin-3-yloxy)- 161 acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 485 (±)-(4-Chloro-2-{2-[2-(5,6-dimethoxy-pyridin-3-yloxy)-acetyl]- 316 1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 486 (±)-(4-Chloro-2-{2-[2-(6-methoxy-pyridin-3-yloxy)-acetyl]-1,2,3,4- 371 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 487 (±)-(4-Chloro-2-{2-[2-(4-chloro-pyridin-3-yloxy)-acetyl]-1,2,3,4- 400 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 488 (±)-(4-Chloro-2-{2-[2-(3-methyl-indol-1-yl)-acetyl]-1,2,3,4- 108 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 489 (±)-(4-Chloro-2-{2-[2-(5-methoxy-indol-1-yl)-acetyl]-1,2,3,4- 319 tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid 490 (±)-{4-Chloro-2-[2-(2-chloro-benzylcarbamoyl)-1,2,3,4-tetrahydro- 15.1 isoquinolin-1-yl]-phenoxy}-acetic acid 491 (±)-{4-Chloro-2-[2-(3-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro- 19.8 isoquinolin-1-yl]-phenoxy}-acetic acid 492 (±)-[2-(2-Benzylcarbamoyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-4- 16.6 chloro-phenoxy]-acetic acid 493 (±)-[4-Chloro-2-(2-phenethylcarbamoyl-1,2,3,4-tetrahydro- 22.5 isoquinolin-1-yl)-phenoxy]-acetic acid 494 (±)-{4-Chloro-2-[2-(4-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro- 17 isoquinolin-1-yl]-phenoxy}-acetic acid 495 (±)-{4-Chloro-2-[2-(2-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro- 24.1 isoquinolin-1-yl]-phenoxy}-acetic acid 496 (±)-[2-(2-Butylcarbamoyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-4- 62.7 chloro-phenoxy]-acetic acid 497 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-7-(4-fluoro-phenyl) 793 3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 498 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-7-pyrimidin-5-yl-3,4- 381 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 499 (±)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-1,3-dihydro-isoindole- 25.4 2-carboxylic acid benzyl ester 500 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5-fluoro-1,3-dihydro- 12.9 isoindole-2-carboxylic acid benzyl ester 501 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-4-fluoro-1,3-dihydro- 8.12 isoindole-2-carboxylic acid benzyl ester 502 (±)-(4-Chloro-2-{2-[2-(2-methoxy-phenoxy)-acetyl]-2,3-dihydro- 56.2 1H-isoindol-1-yl}-phenoxy)-acetic acid 503 {4-Chloro-2-[2-trans-(2-phenyl-cyclopropanecarbonyl)-2,3- 11.2 dihydro-1H-isoindol-1-yl]-phenoxy}-acetic acid 504 (±)-(4-Chloro-2-{2-[2-(4-fluoro-phenoxy)-acetyl]-2,3-dihydro-1H- 33 isoindol-1-yl}-phenoxy)-acetic acid 505 (±)-{4-Chloro-2-[2-(3-pyridin-3-yl-propionyl)-2,3-dihydro-1H- 189 isoindol-1-yl]-phenoxy}-acetic acid 506 (±)-{4-Chloro-2-[2-(3-o-tolyl-propionyl)-2,3-dihydro-1H-isoindol-1- 78.8 yl]-phenoxy}-acetic acid 507 (±)-{4-Chloro-2-[2-(2-indol-1-yl-acetyl)-2,3-dihydro-1H-isoindol-1- 129 yl]-phenoxy}-acetic acid 508 (±)-(4-Chloro-2-{2-[3-(1-ethyl-2-methyl-1H-indol-3-yl)-propionyl]- 127 2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid 509 (±)-(4-Chloro-2-{2-[2-(quinolin-8-yloxy)-acetyl]-2,3-dihydro-1H- 37.8 isoindol-1-yl}-phenoxy)-acetic acid 510 (±)-(4-Chloro-2-{2-[3-(2-methyl-1H-indol-3-yl)-propionyl]-2,3- 180 dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid 511 (±)-(4-Chloro-2-{2-[3-(5-methoxy-1H-indol-3-yl)-propionyl]-2,3- 14.8 dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid 512 (±)-(4-Chloro-2-{2-[2-(2,6-dimethyl-pyridin-3-yloxy)-acetyl]-2,3- 42.5 dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid 513 (±)-(4-Chloro-2-{2-[3-(1-methyl-1H-indol-3-yl)-propionyl]-2,3- 25.9 dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid 514 (±)-{4-Chloro-2-[2-(3-2,3-dihydro-indol-1-yl-propionyl)-2,3- 38.8 dihydro-1H-isoindol-1-yl]-phenoxy}-acetic acid 515 (±)-{4-Chloro-2-[2-(3-3,4-dihydro-2H-quinolin-1-yl-propionyl)-2,3- 60.1 dihydro-1H-isoindol-1-yl]-phenoxy}-acetic acid 516 (±)-{4-Chloro-2-[2-(3-indazol-1-yl-propionyl)-2,3-dihydro-1H- 12.5 isoindol-1-yl]-phenoxy}-acetic acid 517 (±)-(4-Chloro-2-{2-[3-(3-fluoro-phenoxy)-propionyl]-2,3-dihydro- 123 1H-isoindol-1-yl}-phenoxy)-acetic acid 518 (±)-(4-Chloro-2-{2-[2-(5-methoxy-benzo[d]isoxazol-3-yl)-acetyl]- 20.1 2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid 519 (±)-(4-Chloro-2-{2-[3-(3-methyl-indol-1-yl)-propionyl]-2,3-dihydro- 37.4 1H-isoindol-1-yl}-phenoxy)-acetic acid 520 (±)-(4-Chloro-2-{2-[3-(4-fluoro-phenoxy)-propionyl]-2,3-dihydro- 130 1H-isoindol-1-yl}-phenoxy)-acetic acid 521 (±)-(4-Chloro-2-{2-[2-(2-chloro-benzyloxy)-acetyl]-2,3-dihydro- 9.11 1H-isoindol-1-yl}-phenoxy)-acetic acid 522 (±)-(4-Chloro-2-{2-[3-(2-fluoro-phenoxy)-propionyl]-2,3-dihydro- 11.7 1H-isoindol-1-yl}-phenoxy)-acetic acid 523 (4-Chloro-2-{2-trans-[2-(3-fluoro-phenyl)-cyclopropanecarbonyl]- 40.5 2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid 524 (4-Chloro-2-{2-trans-[2-(3-chloro-phenyl)-cyclopropanecarbonyl]- 81.3 2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid 525 (4-Chloro-2-{2-trans-[2-(2-fluoro-phenyl)-cyclopropanecarbonyl]- 13.5 2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid 526 (±)-{4-Chloro-2-[5-fluoro-2-(3-indazol-1-yl-propionyl)-2,3-dihydro- 4.53 1H-isoindol-1-yl]-phenoxy}-acetic acid 527 (4-Chloro-2-{2-[3-(5-fluoro-indazol-1-yl)-propionyl]-2,3-dihydro- 8.12 1H-isoindol-1-yl}-phenoxy)-acetic acid (enantiomer 1) 528 (4-Chloro-2-{2-[3-(4-fluoro-3-methyl-indazol-1-yl)-propionyl]-2,3- 33.2 dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid (enantiomer 1) 529 (4-Chloro-2-{2-[3-(4-chloro-3-methyl-indazol-1-yl)-propionyl]-2,3- 78 dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid (enantiomer 1) 530 (4-Chloro-2-{2-[3-(7-fluoro-3-methyl-indazol-1-yl)-propionyl]-2,3- 101 dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid (enantiomer 1) 531 (4-Chloro-2-{2-[3-(6-fluoro-3-methyl-indazol-1-yl)-propionyl]-2,3- 30.9 dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid (enantiomer 1) 532 (4-Chloro-2-{2-[3-(6-chloro-3-methyl-indazol-1-yl)-propionyl]-2,3- 40.7 dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid (enantiomer 1) 533 (4-Chloro-2-{2-[3-(3-methyl-indazol-1-yl)-propionyl]-2,3-dihydro- 6.09 1H-isoindol-1-yl}-phenoxy)-acetic acid (enantiomer 1) 534 (4-Chloro-2-{2-[3-(6-fluoro-indazol-1-yl)-propionyl]-2,3-dihydro- 12.9 1H-isoindol-1-yl}-phenoxy)-acetic acid (enantiomer 1) 535 (4-Chloro-2-{2-[3-(4-fluoro-indazol-1-yl)-propionyl]-2,3-dihydro- 15.1 1H-isoindol-1-yl}-phenoxy)-acetic acid (enantiomer 1) 536 (4-Chloro-2-{2-[3-(7-chloro-indazol-1-yl)-propionyl]-2,3-dihydro- 110 1H-isoindol-1-yl}-phenoxy)-acetic acid (enantiomer 1) 537 (4-Chloro-2-{2-[3-(7-fluoro-indazol-1-yl)-propionyl]-2,3-dihydro- 25.8 1H-isoindol-1-yl}-phenoxy)-acetic acid (enantiomer 1) 538 (4-Chloro-2-{2-[3-(4-fluoro-3-methyl-indazol-1-yl)-propionyl]-2,3- 704 dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid (enantiomer 2) 539 (4-Chloro-2-{2-[3-(4-chloro-3-methyl-indazol-1-yl)-propionyl]-2,3- 235 dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid (enantiomer 2) 540 (4-Chloro-2-{2-[3-(7-fluoro-3-methyl-indazol-1-yl)-propionyl]-2,3- 633 dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid (enantiomer 2) 541 (4-Chloro-2-{2-[3-(6-fluoro-3-methyl-indazol-1-yl)-propionyl]-2,3- 865 dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid (enantiomer 2) 542 (4-Chloro-2-{2-[3-(6-chloro-3-methyl-indazol-1-yl)-propionyl]-2,3- 881 dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid (enantiomer 2) 543 (4-Chloro-2-{2-[3-(5-fluoro-indazol-1-yl)-propionyl]-2,3-dihydro- 353 1H-isoindol-1-yl}-phenoxy)-acetic acid (enantiomer 2) 544 (4-Chloro-2-{2-[3-(5-chloro-indazol-1-yl)-propionyl]-2,3-dihydro- 340 1H-isoindol-1-yl}-phenoxy)-acetic acid (enantiomer 2) 545 (4-Chloro-2-{2-[3-(3-methyl-indazol-1-yl)-propionyl]-2,3-dihydro- 982 1H-isoindol-1-yl}-phenoxy)-acetic acid (enantiomer 2) 546 (4-Chloro-2-{2-[3-(6-fluoro-indazol-1-yl)-propionyl]-2,3-dihydro- 210 1H-isoindol-1-yl}-phenoxy)-acetic acid (enantiomer 2) 547 (4-Chloro-2-{2-[3-(4-fluoro-indazol-1-yl)-propionyl]-2,3-dihydro- 272 1H-isoindol-1-yl}-phenoxy)-acetic acid (enantiomer 2) 548 (4-Chloro-2-{2-[3-(7-chloro-indazol-1-yl)-propionyl]-2,3-dihydro- 715 1H-isoindol-1-yl}-phenoxy)-acetic acid (enantiomer 2) 549 (4-Chloro-2-{2-[3-(6-chloro-indazol-1-yl)-propionyl]-2,3-dihydro- 180 1H-isoindol-1-yl}-phenoxy)-acetic acid (enantiomer 2) 550 (4-Chloro-2-{2-[3-(4-chloro-indazol-1-yl)-propionyl]-2,3-dihydro- 240 1H-isoindol-1-yl}-phenoxy)-acetic acid (enantiomer 2) 551 (4-Chloro-2-{2-[3-(7-fluoro-indazol-1-yl)-propionyl]-2,3-dihydro- 292 1H-isoindol-1-yl}-phenoxy)-acetic acid (enantiomer 2) 552 (±)-{4-Chloro-2-[2-(2-fluoro-benzylcarbamoyl)-2,3-dihydro-1H- 19.6 isoindol-1-yl]-phenoxy}-acetic acid 553 (±)-{4-Chloro-2-[2-(3-fluoro-benzylcarbamoyl)-2,3-dihydro-1H- 17.4 isoindol-1-yl]-phenoxy}-acetic acid 554 (±)-{4-Chloro-2-[2-(4-fluoro-benzylcarbamoyl)-2,3-dihydro-1H- 25.7 isoindol-1-yl]-phenoxy}-acetic acid 555 (±)-[2-(2-Benzylcarbamoyl-2,3-dihydro-1H-isoindol-1-yl)-4-chloro- 14.5 phenoxy]-acetic acid 556 (±)-[4-Chloro-2-(2-phenethylcarbamoyl-2,3-dihydro-1H-isoindol- 11.7 1-yl)-phenoxy]-acetic acid 557 (±)-{4-Chloro-2-[2-(2-chloro-benzylcarbamoyl)-2,3-dihydro-1H- 13.7 isoindol-1-yl]-phenoxy}-acetic acid 558 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-4,5-dichloro-1,3- 16.9 dihydro-isoindole-2-carboxylic acid benzyl ester 559 (±)-1-(2-Carboxymethoxy-5-chloro-phenyl)-4,5-difluoro-1,3- 11.2 dihydro-isoindole-2-carboxylic acid benzyl ester 560 {4-Chloro-2-[(S)-2-((1R,2R)-2-o-tolyl-cyclopropanecarbonyl)- 3.27 1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid 561 {4-Chloro-2-[(S)-2-((1S,2S)-2-o-tolyl-cyclopropanecarbonyl)- 274 1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid 562 (4-Chloro-2-{(S)-2-[(1R,2R)-2-(2-trifluoromethyl-phenyl)- 3.75 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 563 (4-Chloro-2-{(S)-2-[(1S,2S)-2-(2-trifluoromethyl-phenyl)- 264 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 564 (4-Chloro-2-{(S)-2-[(1R,2R)-2-(3-chloro-phenyl)- 4.29 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 565 (4-Chloro-2-{(S)-2-[(1R,2R)-2-(3-fluoro-phenyl)- 2.64 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 566 (4-Chloro-2-{(S)-2-[(1R,2R)-2-(4-fluoro-phenyl)- 2.17 cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}- phenoxy)-acetic acid 567 (S)-benzyl 1-(5-chloro-2-(2-cyanamido-2-oxoethoxy)phenyl)-3,4- 370 dihydroisoquinoline-2(1H)-carboxylate 568 (S)-1-[5-Chloro-2-(2-oxo-2-trifluoromethanesulfonylamino- 9.18 ethoxy)-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 569 (S)-1-(5-Chloro-2-hydroxycarbamoylmethoxy-phenyl)-3,4- 120 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 570 (±)-1-[5-Chloro-2-(1H-tetrazol-5-ylmethoxy)-phenyl]-3,4-dihydro- 355 1H-isoquinoline-2-carboxylic acid benzyl ester 571 (S)-1-[5-Chloro-2-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2- 55 ylmethoxy)-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 572 (±)-1-[5-Chloro-2-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3- 325 ylmethoxy)-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester 573 (±)-1-[5-Chloro-2-(3-hydroxy-isoxazol-5-ylmethoxy)-phenyl]-3,4- 15.3 dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester

Radioligand Displacement Assay-Human Serum Albumin (HSA):

Radioligand displacement assay in presence of human serum albumin (HSA) was performed as described above, with following modifications. Binding-Buffer-HSA: Binding-buffer+0.5% Sigma Albumin from Human serum A1887 (instead of 0.1% BSA). A volume of 25 μl test compound, previously diluted in Binding-Buffer—HSA was placed into each well. After addition of 75 μl Binding-Buffer-HSA, 50 μl of ³H-PGD₂ (at 2.5 nM (220.000 dpm/well) from ANAWA ART0662) was added to each well. Remaining protocol was identical as described above.

REFERENCES

-   Shimizu T, Yamashita A, Hayaishi O, Specific binding of     prostaglandin D2 to rat brain synaptic membranes. J. Biol.     Chem. 1982. Vol. 257:13570-13575. -   Fortini A, Modesti P A, Abbate R, Gensini G F, Neri Semen G G.     Heparin does not interfere with prostacyclin and prostaglandin D2     binding to platelets. Thromb. Res. 1985. Vol. 40:319-328. -   Sawyer N, Cauchon E, Chateauneuf A, Cruz R P, Nicholson D W, Metters     K M, O'Neill G P, Gervais F G. Molecular pharmacology of the human     PGD2 receptor CRTH2. Br. J. of Pharmacol. 2002. Vol. 137:1163-1172     Eosinophil Shape Change Assay with Human Plasma

After obtaining informed consent, blood samples were drawn by venipuncture according to the protocol approved by the ethics committee of Basel, Switzerland. Polymorphonuclear leukocytes (containing eosinophils, basophils and neutrophils) were isolated using the Polymorphprep™ method (Axis-Shield). In brief, anticoagulated whole blood was layered onto a Polymorphprep gradient (density 1.113 g/ml) and centrifuged at 500 g for 30 min. The polymorphonuclear cell fraction was harvested and depleted for erythrocytes by hypotonic saline lysis.

The polymorphonuclear cells were resuspended in assay buffer (1×PBS with Ca²⁺/Mg²⁺supplemented with 0.1% BSA, 10 mM HEPES, and 10 mM Glucose, pH 7.4) at 5×10⁶ cells/ml and stained with anti-CD49d-APC ((APC=Allophycocyanin) for 1 hour at RT. Test compounds, at various concentrations, were preincubated 10 min in human plasma (anticoagulated with a thrombin inhibitor). Then, human plasma was added to the polymorphonuclear cells to 50% of final assay volume with polymorphonuclear cells at 4×10⁶ cells/ml. After incubation for 10 minutes at 37° C., the polymorphonuclear cells were activated for 5 min at 37° C. by addition of PGD₂ at 100 nM final concentration. Activation was stopped by addition of 0.5 ml paraformaldehyde (1%).

Immediately after fixation with paraformaldehyde, the samples were analyzed by FACSCanto flow cytometer (BD Biosciences) and target cells were identified by their forward-scatter (FSC) and side-scatter (SSC) characteristics. Eosinophils were identified by the anti-CD49d-APC signal and their characteristic side-scatter (SSC) profile. Shape change responses, indicative of eosinophil activation, were quantified as the percent of cells with an increased forward-scatter.

Intracellular Calcium Mobilization Assay (FLIPR):

Cells (HEK-293), stably expressing the hCRTH2 receptor under the control of the cytomegalovirus promoter from a single insertion of the expression vector pcDNA5 (Invitrogen), are grown to confluency in DMEM (low glucose, Gibco) medium supplemented with 10% fetal calf serum (Bioconcept, Switzerland) under standard mammalian cell culture conditions (37° C. in a humidified atmosphere of 5% CO₂). Cells are detached from culture dishes using a dissociation buffer (0.02% EDTA in PBS, Gibco) for 1 min, and collected by centrifugation at 200 g at rt for 5 min in assay buffer (equal parts of Hank's BSS (HBSS, Bioconcept) and DMEM (low glucose, without phenol red, Gibco)). After incubation for 45 min (37° C. and 5% CO₂) in the presence of 1 μM Fluo-4 and 0.04% Pluronic F-127 (both Molecular Probes), and 20 mM HEPES (Gibco) in assay buffer, the cells are washed with and resuspended in assay buffer, then seeded onto 384-well FLIPR assay plates (Greiner) at 50,000 cells in 66 μl per well, and sedimented by centrifugation.

Stock solutions of test compounds are made up at a concentration of 10 mM in DMSO, and serially diluted in assay buffer to concentrations required for inhibition dose response curves. Prostaglandin D₂ (Biomol, Plymouth Meeting, PA) is used as an agonist.

A FLIPR Tetra instrument (Molecular Devices) is operated according to the manufacturer's standard instructions, adding 4 μl of test compound dissolved at 10 mM in DMSO and diluted prior to the experiment in assay buffer to obtain the desired final concentration. 10 μl of 80 nM prostaglandin D₂ (Biomol, Plymouth Meeting, PA) in assay buffer, supplemented with 0.8% bovine serum albumin (fatty acid content <0.02%, Sigma), is then added to obtain a final concentration of 10 nM and 0.1%, respectively. Changes in fluorescence are monitored before and after the addition of test compounds at λ_(ex)=488 nm and λ_(em)=540 nm. Emission peak values above base level after prostaglandin D₂ addition are exported after base line subtraction. Values are normalized to high-level control (no test compound added) after subtraction of base line value (no prostaglandin D₂ added). The program XLIfit 3.0 (IDBS) is used to fit the data to a single site dose response curve of the equation (A+((B−A)/(1+((C/x)̂D)))) and to calculate the IC₅₀ values. 

1. A compound of formula (I):

wherein X represents —NH—, —O— or a bond; Y represents (C₁-C₄)alkandiyl; Z represents O or S; n represents 0 or 1; R¹ represents (C₄-C₆)alkyl; (C₁-C₄)alkyl which is mono-substituted with (C₃-C₆)cycloalkyl, (C₁-C₄)alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted aryl-(C₁-C₂)alkoxy, optionally substituted heteroaryl-(C₁-C₂)alkoxy, optionally substituted heteroarylsulfanyl or —NR⁸R⁹; (C₂-C₄)alkenyl which is mono-substituted with optionally substituted aryl; (C₂-C₄)alkynyl which is mono-substituted with optionally substituted aryl; (C₃-C₆)cycloalkyl which is mono- or di-substituted with (C₁-C₄)alkyl, mono-substituted with (C₁-C₄)alkoxy, mono-substituted with optionally substituted aryl or mono-substituted with optionally substituted heteroaryl; optionally substituted aryl; or a 10-membered partially unsaturated ring system; R² represents hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)fluoro alkyl, halogen, (C₁-C₄)alkylsulfonyl, phenylsulfonyl or (C₁-C₄)alkylsulfonylamino; R³ represents hydrogen, (C₁-C₄)alkoxy or halogen; R⁴ represents hydrogen, (C₁-C₄)alkoxy, halogen, (C₁-C₄)alkylsulfonyl, optionally substituted aryl or optionally substituted heteroaryl; R⁵ represents hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)fluoroalkyl, halogen, cyano, —CONH₂, optionally substituted aryl, optionally substituted heteroaryl, (C₁-C₄)alkylsulfonyl, phenylsulfonyl or dimethylamino-sulfonyl; and R⁶ represents hydrogen or halogen; or R⁵ and R⁶ together form a methylendioxy-group; R⁷ represents hydrogen or methyl; R⁸ represents hydrogen or methyl; R⁹ represents optionally substituted aryl, optionally substituted arylsulfonyl or optionally substituted heteroarylsulfonyl; and R¹⁰ represents —C(O)OH, —C(O)NH—CN, —C(O)NH—OH, —C(O)NH—S(O)₂CF₃ or optionally substituted heteroaryl; with the proviso that R¹ is different from optionally substituted aryl if X represents —NH— or a bond; or a salt thereof.
 2. The compound according to claim 1, wherein X represents —O— or a bond; Y represents methandiyl; Z represents O; n represents 0 or 1; R¹ represents (C₁-C₂)alkyl which is mono-substituted with optionally substituted aryl, optionally substituted heteroaryl or optionally substituted aryl-(C₁-C₂)alkoxy; or cyclopropyl which is mono-substituted with optionally substituted aryl; R² represents hydrogen, trifluoromethyl or fluoro; R³ represents hydrogen or fluoro; R⁴ represents hydrogen; R⁵ represents halogen or cyano; R⁶ represents hydrogen; R⁷ represents hydrogen; and R¹⁰ represents —C(O)OH; or a salt thereof.
 3. The compound according to claim 1, wherein X represents —O—; or a salt thereof.
 4. The compound according to claim 1, wherein X represents a bond; or a salt thereof.
 5. The compound according to claim 1, wherein Z represents O; or a salt thereof.
 6. The compound according to claim 1, wherein R¹ represents (C₁-C₄)alkyl which is mono-substituted with (C₃-C₆)cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted aryl-(C₁-C₂)alkoxy or optionally substituted heteroaryl-(C₁-C₂)alkoxy; or cyclopropyl which is mono- or di-substituted with (C₁-C₄)alkyl, mono-substituted with optionally substituted aryl or mono-substituted with optionally substituted heteroaryl; or a salt thereof.
 7. The compound according to claim 1, wherein R² represents hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)fluoroalkyl or halogen; or a salt thereof.
 8. The compound according to claim 1, wherein R⁴ represents hydrogen or halogen; or a salt thereof.
 9. The compound according to claim 1, wherein R⁵ represents halogen or cyano; or a salt thereof.
 10. The compound according to claim 1, wherein R⁷ represents hydrogen; or a salt thereof.
 11. The compound according to claim 1, wherein R¹⁰ represents —C(O)OH; or a salt thereof.
 12. The compound according to claim 1 comprising: 1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-[2-((S)-1-Carboxy-ethoxy)-5-fluoro-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-methyl-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(5-Bromo-2-carboxymethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 7-Bromo-1-(2-carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-4,5-difluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 5-Bromo-1-(2-carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-[2-((R)-1-Carboxy-ethoxy)-5-fluoro-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-fluoro-phenyl)-6,7-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(5-Bromo-2-carboxymethoxy-phenyl)-6,7-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-cyano-phenyl)-6,7-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-fluoro-phenyl)-5-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-[2-((R)-1-Carboxy-ethoxy)-5-cyano-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-fluoro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-cyano-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-dimethylsulfamoyl-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-cyano-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-trifluoromethyl-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-isopropyl-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(6-Carboxymethoxy-benzo[1,3]dioxol-5-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-methoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; (S)-1-(2-Carboxymethoxy-5-cyano-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; (S)-1-[2((R)-1-Carboxy-ethoxy)-5-fluoro-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; (S)-1-[2-((S)-1-Carboxy-ethoxy)-5-fluoro-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; {4-Fluoro-2-[(S)-2-((trans)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; (S)-1-(2-Carboxymethoxy-5-cyano-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-3,5-difluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-fluoro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-fluoro-phenyl)-5-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-fluoro-phenyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-fluoro-phenyl)-7-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-fluoro-phenyl)-5-chloro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-fluoro-phenyl)-5-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 5-Bromo-1-(2-carboxymethoxy-5-fluoro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-fluoro-phenyl)-7-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-fluoro-phenyl)-5,7-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-5,7-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-cyano-phenyl)-5,7-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; {2-[2-(2-Benzo[d]isoxazol-3-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic acid; {4-Fluoro-2-[2-(3-methyl-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {4-Fluoro-2-[2-(2-naphthalen-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {4-Fluoro-2-[2-(2-quinolin-7-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {4-Fluoro-2-[2-(2-quinolin-6-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {2-[2-(2-2,3-Dihydro-benzo[1,4]dioxin-6-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic acid; {4-Fluoro-2-[2-(3-1H-indol-3-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; (2-{2-[3-(1-Ethyl-2-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic acid; (2-{2-[3-(2,6-Dichloro-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic acid; (4-Fluoro-2-{2-[3-(2-fluoro-phenoxy)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; [4-Fluoro-2-(2-{2-[4-(5-methyl-tetrazol-1-yl)-phenyl]-acetyl}-1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid; (2-{2-[3-(6-Chloro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic acid; (4-Fluoro-2-{2-[2-(2-methyl-thiazol-4-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; {2-[2-(2-Benzo[b]thiophen-3-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic acid; {2-[2-(3-Benzothiazol-2-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic acid; {2-[2-(2-Biphenyl-4-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic acid; {4-Fluoro-2-[2-(2-indol-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {2-[2-(2-1H-Benzoimidazol-2-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic acid; {2-[2-(2-1,3-Dihydro-isoindol-2-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic acid; (4-Fluoro-2-{2-[3-(5-methoxy-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Fluoro-2-{2-[3-(2-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Fluoro-2-{2-[3-(1-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; {4-Fluoro-2-[2-(trans-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {4-Chloro-2-[2-(2-cyclopropyl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {4-Chloro-2-[2-(2H-chromene-3-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {4-Chloro-2-[2-(3-methoxy-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; (4-Chloro-2-{2-[2-(2-chloro-phenyl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; {4-Chloro-2-[2-(2-indol-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; (4-Chloro-2-{2-[3-(2-methyl-1H-indol-3-ye-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(5-methoxy-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[2-(2,6-dimethyl-pyridin-3-yloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(1-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; {4-Chloro-2-[2-(1,2,3,4-tetrahydro-naphthalene-2-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {2-[2-(2-Benzoimidazol-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-chloro-phenoxy}-acetic acid; {4-Chloro-2-[2-(2-3,4-dihydro-2H-quinolin-1-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {4-Chloro-2-[2-(2-indazol-2-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; (4-Chloro-2-{2-[3-(3-trifluoromethyl-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-trans-[2-(2-chloro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(1-phenyl-1H-imidazol-2-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(4-oxo-2-phenyl-thiazolidin-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; [4-Chloro-2-(2-{3-[3-(2,3-dimethyl-phenyl)-3H-imidazol-4-yl]-propionyl}-1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid; (2-{2-[2-(Biphenyl-2-yloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-chloro-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(3-fluoro-phenoxy)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; {4-Chloro-2-[2-(3-p-tolyloxy-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; (4-Chloro-2-{2-[3-(4-chloro-phenoxy)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(2-trifluoromethyl-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[2-(5-fluoro-1H-indol-3-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[2-(6-methoxy-benzofuran-3-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[4-(4-chloro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; {4-Chloro-2-[2-(3-m-tolyloxy-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; (4-Chloro-2-{2-[3-(3-chloro-phenoxy)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[2-(5-chloro-1H-indol-3-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; {4-Chloro-2-[2-(4-p-tolyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; (4-Chloro-2-{2-[2-(5-chloro-benzo[b]thiophen-3-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[2-(5-methoxy-1H-indol-2-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[2-(5-methyl-benzo[d]isoxazol-3-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[2-(5-methoxy-benzo[d]isoxazol-3-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(4-fluoro-phenoxy)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[4-(4-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; {4-Chloro-2-[2-(3-o-tolyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {2-[2-(2-Benzyloxy-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-chloro-phenoxy}-acetic acid; (4-Chloro-2-{2-[2-(2-chloro-benzyloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; {4-Chloro-2-[2-(4-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; (4-Chloro-2-{2-[4-(3-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[4-(2,3-dichloro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; {4-Chloro-2-[2-(4-m-tolyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {4-Chloro-2-[2-(4-o-tolyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; (4-Chloro-2-{2-[4-(3-chloro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[4-(2-chloro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[4-(3-methoxy-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[4-(2-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; {4-Chloro-2-[2-(trans-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {4-Chloro-2-[5-fluoro-2-(trans-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {4-Chloro-2-[5-fluoro-2-(3-o-tolyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {2-[2-(2-Benzyloxy-acetyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-chloro-phenoxy}-acetic acid; (4-Chloro-2-{2-[2-(2-chloro-benzyloxy)-acetyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; {4-Chloro-2-[5-fluoro-2-(4-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {4-Chloro-2-[5-fluoro-2-(3-phenyl-propynoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {4-Fluoro-2-[2-(3-phenyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; [4-Fluoro-2-(2-phenylacetyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid; {4-Fluoro-2-[2-(2-phenoxy-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {2-[2-(2-Benzyloxy-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic acid; {4-Fluoro-2-[2-(4-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; (4-Fluoro-2-{2-[3-(2-methoxy-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Fluoro-2-{2-[3-(3-methoxy-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Fluoro-2-{2-[3-(4-methoxy-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (2-{2-[3-(2-Chloro-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic acid; (2-{2-[3-(3-Chloro-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic acid; (2-{2-[3-(4-Chloro-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic acid; {4-Fluoro-2-[2-(3-o-tolyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {4-Fluoro-2-[2-(2-naphthalen-2-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {4-Fluoro-2-[2-(2-o-tolyloxy-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; (4-Fluoro-2-{2-[2-(1-methyl-1H-indol-3-yl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (2-{2-[2-(2-Chloro-phenoxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic acid; (4-Fluoro-2-{2-[3-(2-fluoro-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; {4-Fluoro-2-[2-(2-indan-2-yl-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; (4-Fluoro-2-{2-[(E)-3-(2-fluoro-phenyl)-acryloyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; {4-Fluoro-2-[2-((E)-3-o-tolyl-acryloyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {4-Fluoro-2-[2-(5-phenyl-pentanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {4-Fluoro-2-[2-(3-phenoxy-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; (4-Fluoro-2-{2-[3-(4-methanesulfonyl-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; {2-[2-(3-2,3-Dihydro-indol-1-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic acid; {4-Fluoro-2-[2-(3-o-tolyloxy-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; (4-Fluoro-2-{2-[2-(2-fluoro-phenoxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Fluoro-2-{2-[4-(2-methoxy-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (2-{2-[2-(2-Chloro-benzyloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic acid; (4-Chloro-2-{2-[(trans)-2-(3-chloro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; {4-Chloro-2-[2-((trans)-2-o-tolyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; (4-Chloro-2-{2-[(trans)-2-(2-trifluoromethyl-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[trans-2-(4-chloro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[trans-2-(2,4-dichloro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[trans-2-(2-methoxy-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[trans-2-(2-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(3-phenyl-3H-[1,2,3]triazol-4-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[2-(3-phenyl-3H-[1,2,3]triazol-4-ylsulfanyl)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; 1-(2-Carboxymethoxy-5-fluoro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-chloro-benzyl ester; 1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-chloro-benzyl ester; 1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,2-dimethyl-propyl ester; 1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid butyl ester; 1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-methoxy-phenyl ester; 1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid phenyl ester; 1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-chloro-phenyl ester; 1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid isobutyl ester; 1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-methoxy-ethyl ester; 1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-methoxy-phenyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-chloro-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-chloro-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-(2-chloro-phenyl)-ethyl ester; 1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-(2-chloro-phenyl)-ethyl ester; 1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3-chloro-phenyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-(2-chloro-phenyl)-ethyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-fluoro-phenyl)-7-ethanesulfonyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-methanesulfonyl-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(5-Benzenesulfonyl-2-carboxymethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-ethanesulfonyl-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-fluoro-phenyl)-5-methanesulfonyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-fluoro-phenyl)-5-ethanesulfonyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(5-Benzenesulfonyl-1-(2-carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-pyrimidin-5-yl-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(4-Carboxymethoxy-4′-fluoro-biphenyl-3-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; (2-{2-[2-(3-Chloro-benzyloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic acid; (2-{2-[2-(4-Chloro-benzyloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic acid; (4-Fluoro-2-{2-[2-(2-methyl-benzyloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Fluoro-2-{2-[2-(3-methyl-benzyloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Fluoro-2-{2-[2-(4-methyl-benzyloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Fluoro-2-{2-[2-(3-methoxy-benzyloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Fluoro-2-{2-[2-(4-methoxy-benzyloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Fluoro-2-{2-[2-(1-methyl-1H-pyrazol-3-ylmethoxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Fluoro-2-{2-[2-(2-methoxy-benzyloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; [2-(2-Benzylcarbamoyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-4-fluoro-phenoxy]-acetic acid; [4-Fluoro-2-(2-phenethylcarbamoyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid; {4-Fluoro-2-[2-(2-methoxy-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {4-Chloro-2-[2-(2-methoxy-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {2-[2-(2-Chloro-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic acid; (2-{2-[2-(2-Chloro-phenyl)-ethylcarbamoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic acid; {2-[2-(2-Benzenesulfonylamino-acetyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-4-fluoro-phenoxy}-acetic acid; (2-{2-[2-(3,5-Dimethyl-isoxazole-4-sulfonylamino)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic acid; (4-Fluoro-2-{2-[2-(3-fluoro-benzenesulfonylamino)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Fluoro-2-{2-[2-(2-fluoro-benzenesulfonylamino)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (2-{2-[2-(3,4-Difluoro-benzenesulfonylamino)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic acid; (2-{2-[2-(N-Benzenesulfonyl-N-methyl-amino)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-4-fluoro-phenoxy)-acetic acid; [4-Fluoro-2-(2-{2-[N-(3-fluoro-benzenesulfonyl)-N-methyl-amino]-acetyl}-1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid; [2-(2-{2-[N-(3,4-Difluoro-benzenesulfonyl)-N-methyl-amino]-acetyl}-1,2,3,4-tetrahydro-isoquinolin-1-yl)-4-fluoro-phenoxy]-acetic acid; 1-(5-Carbamoyl-2-carboxymethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-[2-Carboxymethoxy-5-(5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-4-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-6-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-[2-(3-Carboxy-propoxy)-5-fluoro-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; {4-Cyano-2-[2-(trans-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; 1-(2-Carboxymethoxy-5-cyano-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; (R)-1-[2-(1-Carboxy-ethoxy)-5-chloro-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; (S)-1-(2-Carboxymethoxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-fluoro-phenyl)-5-methanesulfonylamino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-[1,2,3]triazol-1-yl-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-[1,2,3]triazol-2-yl-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; or {4-Chloro-2-[2-(2-methoxy-benzylthiocarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; or a salt thereof.
 13. The compound according to claim 1 comprising: 1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-bromo-benzyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester; {4-Chloro-2-[(S)-2-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-methoxy-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-fluoro-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-methyl-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-trifluoromethyl-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3-methoxy-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3-fluoro-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3-methyl-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3-trifluoromethyl-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,4-dichloro-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,3-dichloro-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,6-dichloro-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,6-dimethoxy-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,4-dimethyl-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,3-dimethyl-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,6-dimethyl-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,4-difluoro-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,3-difluoro-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,6-difluoro-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,4,6-trimethyl-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-chloro-6-fluoro-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,5-dichloro-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,4-dimethoxy-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,3-dimethoxy-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,6-dimethyl-pyridin-3-ylmethyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3-cyano-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,5-difluoro-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 5-chloro-2-fluoro-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-chloro-5-fluoro-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid cyclohexylmethyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 1-methyl-1H-pyrazol-3-ylmethyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid cyclopentylmethyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid isobutyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid butyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-methoxy-ethyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid cyclopropylmethyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3,5-dimethyl-pyrazol-1-ylmethyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 5-methyl-isoxazol-3-ylmethyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 1,5-dimethyl-1H-pyrazol-3-ylmethyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-chloro-benzyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid thiazol-2-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-(4-methyl-thiazol-5-yl)-ethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 5-methyl-thiazol-2-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-methyl-thiazol-2-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-methyl-thiazol-5-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phen yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-methyl-thiazol-4-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3-methyl-isoxazol-5-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-methyl-isoxazol-3-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3,5-dimethyl-isoxazol-4-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid pyrazin-2-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid pyrimidin-4-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid pyrimidin-5-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid phenethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-(3-fluoro-phenyl)-ethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-methyl-2H-pyrazol-3-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,5-dimethyl-2H-pyrazol-3-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-(2-ethyl-5-methyl-2H-pyrazol-3-yl)-ethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3-methyl-3H-imidazol-4-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-(3,5-dimethyl-pyrazol-1-yl)-ethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-methyl-pyrazol-1-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzothiazol-2-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzooxazol-2-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 1-methyl-1H-indazol-3-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid indazol-1-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzo[d]isoxazol-3-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid thiazol-2-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-(4-methyl-thiazol-5-yl)-ethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 5-methyl-thiazol-2-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-methyl-thiazol-2-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-methyl-thiazol-5-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-methyl-thiazol-4-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3-methyl-isoxazol-5-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-methyl-isoxazol-3-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3,5-dimethyl-isoxazol-4-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid pyrazin-2-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid pyrimidin-4-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid phenethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-(3-fluoro-phenyl)-ethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-methyl-2H-pyrazol-3-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,5-dimethyl-2H-pyrazol-3-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-(2-ethyl-5-methyl-2H-pyrazol-3-yl)-ethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3-methyl-3H-imidazol-4-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-(3,5-dimethyl-pyrazol-1-yl)-ethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-methyl-pyrazol-1-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzothiazol-2-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzooxazol-2-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 1-methyl-1H-indazol-3-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid indazol-1-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzo[d]isoxazol-3-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid thiazol-2-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-(4-methyl-thiazol-5-yl)-ethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 5-methyl-thiazol-2-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-methyl-thiazol-2-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-methyl-thiazol-5-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-methyl-thiazol-4-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3-methyl-isoxazol-5-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-methyl-isoxazol-3-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid pyrazin-2-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid pyrimidin-4-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid pyrimidin-5-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid phenethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-(3-fluoro-phenyl)-ethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-methyl-2H-pyrazol-3-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,5-dimethyl-2H-pyrazol-3-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-(2-ethyl-5-methyl-2H-pyrazol-3-yl)-ethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3-methyl-3H-imidazol-4-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-(3,5-dimethyl-pyrazol-1-yl)-ethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-methyl-pyrazol-1-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzothiazol-2-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzooxazol-2-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 1-methyl-1H-indazol-3-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid indazol-1-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzo[d]isoxazol-3-ylmethyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-fluoro-benzyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3-fluoro-benzyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,3-difluoro-benzyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-fluoro-benzyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3-fluoro-benzyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,3-difluoro-benzyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3-fluoro-benzyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-methoxy-benzyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-fluoro-benzyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3-fluoro-benzyl ester; (S)-1-(2-Carboxymethoxy-5-chloro-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2-fluoro-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-methyl-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-methoxy-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-fluoro-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-trifluoromethyl-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 3-chloro-benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-7-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; (4-Chloro-2-{2-[3-(5-fluoro-3-methyl-indol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(6-methoxy-pyrrolo[2,3-b]pyridin-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(4,6-dimethoxy-pyrrolo[2,3-b]pyridin-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(4,6-dimethoxy-indol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; {4-Chloro-2-[2-(3-indol-1-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; (4-Chloro-2-{2-[3-(5-fluoro-indol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(7-chloro-indol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; {4-Chloro-2-[2-(3-pyrrolo[3,2-b]pyridin-1-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; (4-Chloro-2-{2-[3-(4-methoxy-indol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(3-chloro-indazol-1-ye-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(6-methyl-indol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(6-chloro-indol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(4-fluoro-indol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(6-fluoro-indol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(6-methoxy-indol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{(S)-6-fluoro-2-[3-(5-fluoro-indazol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{(S)-6-fluoro-2-[3-(3-methyl-indazol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{(S)-2-[3-(6-chloro-indazol-1-yl)-propionyl]-6-fluoro-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(3-chloro-pyrrolo[2,3-b]pyrazin-5-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[2-(2-methoxy-phenoxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[2-(4-fluoro-phenoxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[2-(quinolin-8-yloxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[2-(4-chloro-phenoxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[trans-2-(4-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[trans-2-(3-chloro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; {4-Chloro-2-[2-(trans-2-o-tolyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; (4-Chloro-2-{2-[trans-2-(2-trifluoromethyl-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[trans-2-(3-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[trans-2-(3-methoxy-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; {4-Chloro-2-[2-(trans-2-m-tolyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {4-Chloro-2-[6-fluoro-2-(trans-2-phenyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; (4-Chloro-2-{6-fluoro-2-[trans-2-(2-trifluoromethyl-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[2-(trans-2-chloro-phenyl)-cyclopropanecarbonyl]-6-fluoro-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; {4-Chloro-2-[6-fluoro-2-(trans-2-o-tolyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; (4-Chloro-2-{2-[2-(2,6-dimethyl-pyridin-3-yloxy)-acetyl]-6-fluoro-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{6-fluoro-2-[3-(1-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; {4-Chloro-2-[6-fluoro-2-(3-o-tolyl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; (4-Chloro-2-{6-fluoro-2-[4-(2-fluoro-phenyl)-butyryl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[2-(2-chloro-benzyloxy)-acetyl]-6-fluoro-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; {4-Chloro-2-[2-(3-2,3-dihydro-indol-1-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; (4-Chloro-2-{2-[3-(3-methyl-indol-1-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; {4-Chloro-2-[2-(3-indazol-1-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {4-Chloro-2-[2-(3-3,4-dihydro-2H-quinolin-1-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; (4-Chloro-2-{2-[2-(2,4-dimethyl-phenoxy)-acetyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(5-methoxy-1-methyl-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; {4-Chloro-2-[2-(3-1H-indol-3-yl-propionyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {4-Chloro-2-[2-(2,2-dimethyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {4-Chloro-2-[2-(2-chloro-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {4-Chloro-2-[2-(3-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; [2-(2-Benzylcarbamoyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-4-chloro-phenoxy]-acetic acid; [4-Chloro-2-(2-phenethylcarbamoyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid; {4-Chloro-2-[2-(4-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; {4-Chloro-2-[2-(2-fluoro-benzylcarbamoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; 1-(2-Carboxymethoxy-5-fluoro-phenyl)-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-5-fluoro-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester; {4-Chloro-2-[2-trans-(2-phenyl-cyclopropanecarbonyl)-2,3-dihydro-1H-isoindol-1-yl]-phenoxy}-acetic acid; (4-Chloro-2-{2-[2-(4-fluoro-phenoxy)-acetyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[2-(quinolin-8-yloxy)-acetyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(5-methoxy-1H-indol-3-yl)-propionyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[2-(2,6-dimethyl-pyridin-3-yloxy)-acetyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(1-methyl-1H-indol-3-yl)-propionyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid; {4-Chloro-2-[2-(3-2,3-dihydro-indol-1-yl-propionyl)-2,3-dihydro-1H-isoindol-1-yl]-phenoxy}-acetic acid; {4-Chloro-2-[2-(3-indazol-1-yl-propionyl)-2,3-dihydro-1H-isoindol-1-yl]-phenoxy}-acetic acid; (4-Chloro-2-{2-[2-(5-methoxy-benzo[d]isoxazol-3-yl)-acetyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(3-methyl-indol-1-yl)-propionyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[2-(2-chloro-benzyloxy)-acetyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(2-fluoro-phenoxy)-propionyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-trans-[2-(3-fluoro-phenyl)-cyclopropanecarbonyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-trans-[2-(2-fluoro-phenyl)-cyclopropanecarbonyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid; {4-Chloro-2-[5-fluoro-2-(3-indazol-1-yl-propionyl)-2,3-dihydro-1H-isoindol-1-yl]-phenoxy}-acetic acid; (4-Chloro-2-{2-[3-(5-fluoro-indazol-1-yl)-propionyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(4-fluoro-3-methyl-indazol-1-yl)-propionyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(6-fluoro-3-methyl-indazol-1-yl)-propionyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(6-chloro-3-methyl-indazol-1-yl)-propionyl]-2,3-dihydro-1H-isoindol-1-yl}phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(3-methyl-indazol-1-yl)-propionyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(6-fluoro-indazol-1-yl)-propionyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(4-fluoro-indazol-1-yl)-propionyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{2-[3-(7-fluoro-indazol-1-yl)-propionyl]-2,3-dihydro-1H-isoindol-1-yl}-phenoxy)-acetic acid; {4-Chloro-2-[2-(2-fluoro-benzylcarbamoyl)-2,3-dihydro-1H-isoindol-1-yl]-phenoxy}-acetic acid; {4-Chloro-2-[2-(3-fluoro-benzylcarbamoyl)-2,3-dihydro-1H-isoindol-1-yl]-phenoxy}-acetic acid; {4-Chloro-2-[2-(4-fluoro-benzylcarbamoyl)-2,3-dihydro-1H-isoindol-1-yl]-phenoxy}-acetic acid; [2-(2-Benzylcarbamoyl-2,3-dihydro-1H-isoindol-1-yl)-4-chloro-phenoxy]-acetic acid; [4-Chloro-2-(2-phenethylcarbamoyl-2,3-dihydro-1H-isoindol-1-yl)-phenoxy]-acetic acid; {4-Chloro-2-[2-(2-chloro-benzylcarbamoyl)-2,3-dihydro-1H-isoindol-1-yl]-phenoxy}-acetic acid; 1-(2-Carboxymethoxy-5-chloro-phenyl)-4,5-dichloro-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester; 1-(2-Carboxymethoxy-5-chloro-phenyl)-4,5-difluoro-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester; {4-Chloro-2-[(S)-2-((1R,2R)-2-o-tolyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid; (4-Chloro-2-{(S)-2-[(1R,2R)-2-(2-trifluoromethyl-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{(S)-2-[(1R,2R)-2-(3-chloro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{(S)-2-[(1R,2R)-2-(3-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (4-Chloro-2-{(S)-2-[(1R,2R)-2-(4-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-phenoxy)-acetic acid; (S)-1-[5-Chloro-2-(2-oxo-2-trifluoromethanesulfonylamino-ethoxy)-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; (S)-1-[5-Chloro-2-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-ylmethoxy)-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; or 1-[5-Chloro-2-(3-hydroxy-isoxazol-5-ylmethoxy)-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester; or a salt thereof.
 14. A pharmaceutical composition comprising a compound according claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 15. The compound according to claim 1, further comprising a pharmaceutically acceptable salt thereof.
 16. A method of preventing or treating a disease or disorder, comprising administering an effective amount of the compound of claim 1 in a subject in need thereof.
 17. A method according to claim 16, wherein the disease or disorder comprises a prostaglandin-mediated disease or disorder. 